Living Donor Decision-Making and the Complex Interplay of Finances and Other Motivators, Barriers, and Facilitators.

INTRODUCTION: The decision to become a living donor requires consideration of a complex, interactive array of factors that could be targeted for clinical, policy, and educational interventions. Our objective was to assess how financial barriers interact with motivators, other barriers, and facilitators during this process. METHODS: Data were obtained from a public survey assessing motivators, barriers, and facilitators of living donation. We used multivariable logistic regression and consensus k-means clustering to assess interactions between financial concerns and other considerations in the decision-making process. RESULTS: Among 1592 respondents, the average age was 43; 74% were female and 14% and 6% identified as Hispanic and Black, respectively. Among employed respondents (72%), 40% indicated that they would not be able to donate without lost wage reimbursement. Stronger agreement with worries about expenses and dependent care challenges was associated with not being able to donate without lost wage reimbursement (OR = 1.2, 95% CI = 1.0-1.3; OR = 1.2, 95% CI = 1.1-1.3, respectively). Four respondent clusters were identified. Cluster 1 had strong motivators and facilitators with minimal barriers. Cluster 2 had barriers related to health concerns, nervousness, and dependent care. Clusters 3 and 4 had financial barriers. Cluster 3 also had anxiety related to surgery and dependent care. CONCLUSIONS: Financial barriers interact primarily with health and dependent care concerns when considering living organ donation. Targeted interventions to reduce financial barriers and improve provider communication regarding donation-related risks are needed.

Sarcopenia is associated with osteopenia and impaired quality of life in children with genetic intrahepatic cholestatic liver disease.

BACKGROUND: Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes. METHODS: Estimated skeletal muscle mass (eSMM) was calculated on dual-energy x-ray absorptiometry obtained in a Childhood Liver Disease Research Network study of children with bile acid synthesis disorders(BASD) alpha-1 antitrypsin deficiency (a1ATd), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Relationships between eSMM, liver disease, and transplant-free survival were assessed. RESULTS: eSMM was calculated in 127 participants (5-18 y): 12 BASD, 41 a1ATd, 33 CIC, and 41 ALGS. eSMM z-score was lower in CIC (-1.6 ± 1.3) and ALGS (-2.1 ± 1.0) than BASD (-0.1 ± 1.1) and a1ATd (-0.5 ± 0.8, p < 0.001). Sarcopenia (defined as eSMM z-score ≤- 2) was present in 33.3% of CIC and 41.5% of ALGS participants. eSMM correlated with bone mineral density in the 4 disease groups (r=0.52-0.55, p < 0.001-0.07), but not serum bile acids, bilirubin, aspartate aminotransferase/platelet ratio index, or clinically evident portal hypertension. Of the 2 patients who died (1 with sarcopenia) and 18 who underwent liver transplant (LT, 4 with sarcopenia), eSMM z-score did not predict transplant-free survival. eSMM z-score correlated with the Physical Pediatric Quality of Life Inventory score (r=0.38-0.53, p = 0.007-0.04) in CIC and a1ATd. CONCLUSION: Severe sarcopenia occurs in some children with ALGS and CIC. The lack of correlation between eSMM and biochemical cholestasis suggests mechanisms beyond cholestasis contribute to sarcopenia. While sarcopenia did not predict transplant-free survival, LT and death were infrequent events. Future studies may define mechanisms of sarcopenia in genetic intrahepatic cholestasis.

Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease.

BACKGROUND AND AIMS: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis. APPROACH AND RESULTS: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS. CONCLUSIONS: Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important.

Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases-Examination of cholestatic liver disease in Alagille syndrome.

The conduct of long-term conventional randomized clinical trials in rare diseases is very difficult, making evidenced-based drug development problematic. As a result, real-world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2-year prospective follow-up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (-1.43 [0.28] -1.99, -0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (-65.2 [16.2] -98.3, -32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real-world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies.

Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children With Monogenic Cholestasis.

OBJECTIVES: To advance our understanding of monogenic forms of intrahepatic cholestasis. METHODS: Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. RESULTS: Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. CONCLUSIONS: In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.

Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study.

Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS-related cholestasis. Two hundred and ninety-three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed JAGGED1 mutations in 91% and NOTCH2 mutations in 4%. Growth was impaired with mean height and weight z-scores of <-1.0 at all ages. Regression analysis revealed that every 10 mg/dL increase in total bilirubin was associated with a decrease in height z-score by 0.10 (P = 0.03) and weight z-score by 0.15 (P = 0.007). Total bilirubin was higher for younger participants (P = 0.03) with a median of 6.9 mg/dL for those less than 1 year old compared with a median of 1.3 mg/dL for participants 13 years or older. The median gamma glutamyl transferase also dropped from 612 to 268 in the same age groups. After adjusting for age, there was substantial within-individual variation of alanine aminotransferase. By 20 years of age, 40% of participants had developed definite portal hypertension. Estimated liver transplant-free survival at the age of 18.5 years was 24%. Conclusions: This is the largest multicenter natural history study of cholestasis in ALGS, demonstrating a previously underappreciated burden of liver disease with early profound cholestasis, a second wave of portal hypertension later in childhood, and less than 25% of patients reaching young adulthood with their native liver. These findings will promote optimization of ALGS management and development of clinically relevant endpoints for future therapeutic trials.

Nonfasted Liver Stiffness Correlates with Liver Disease Parameters and Portal Hypertension in Pediatric Cholestatic Liver Disease.

Elastographic measurement of liver stiffness is of growing importance in the assessment of liver disease. Pediatric experiences with this technique are primarily single center and limited in scope. The Childhood Liver Disease Research Network provided a unique opportunity to assess elastography in a well-characterized multi-institutional cohort. Children with biliary atresia (BA), alpha-1 antitrypsin deficiency (A1ATD), or Alagille syndrome (ALGS) followed in a prospective longitudinal network study were eligible for enrollment in a prospective investigation of transient elastography (FibroScan). Studies were performed in participants who were nonfasted and nonsedated. Liver stiffness measurements (LSMs) were correlated with standard clinical and biochemical parameters of liver disease along with a research definition of clinically evident portal hypertension (CEPH) graded as absent, possible, or definite. Between November 2016 and August 2019, 550 participants with a mean age of 8.8 years were enrolled, 458 of whom had valid LSMs (BA, n = 254; A1ATD, n = 104; ALGS, n = 100). Invalid scans were more common in participants <2 years old. There was a positive correlation between LSM and total bilirubin, international normalized ratio (INR), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), GGT to platelet ratio (GPR), pediatric end-stage liver disease score, AST to platelet ratio index, and spleen size, and a negative correlation with albumin and platelet count in BA, with similar correlations for A1ATD (except AST, ALT, and albumin) and ALGS (except for INR, GGT, GPR, and ALT). Possible or definite CEPH was more common in BA compared to ALGS and A1ATD. LSM was greater in definite versus absent CEPH in all three diseases. Disease-specific clinical and biochemical characteristics of the different CEPH grades were observed. Conclusion: It is feasible to obtain LSMs in children, especially over the age of 2 years. LSM correlates with liver parameters and portal hypertension, although disease-specific patterns exist.

Satisfaction with life and depressive symptoms in living organ donors and non-donors: New insights from the National Living Donor Assistance Center.

BACKGROUND: Previous studies indicate there may be psychological consequences of being unable to serve as a living donor, but these have not been explored in a large national cohort of low-income individuals who initiated living donor evaluation in US transplant centers. METHODS: Using data from 6574 National Living Donor Assistance Center (NLDAC) participants (November 1, 2007-December 31, 2018), we utilized a cross-sectional study design to evaluate short-term depressive symptoms and satisfaction with life in living donors and non-donors (those who were declined or withdrew from evaluation) using the Satisfaction with Life Scale (SWLS) and the PHQ-8, with and without risk adjustment using linear regression. RESULTS: National Living Donor Assistance Center participants originated from 207 US transplant centers. 52% of NLDAC participants responded to the survey (n = 3423; donors = 2848 (58.6% of all donors), non-donors = 575 (33.5% of all non-donors); ncenters  = 201)). Respondents were significantly older, more likely to be female, white, non-Hispanic, married, more educated, more full-time employed, and more likely to be unrelated to the recipient vs non-respondents (all, P < .001). Among survey respondents, donors were significantly younger, more likely to be non-Hispanic, employed, and related to the recipient compared to non-donors (all, P < .05). Higher PHQ-8 scores were correlated with lower SWL scores (r = -.32, P < .001). Both groups displayed high SWLS (donors vs non-donors: 27.1 vs 26.3, P = .002). Both groups had low levels of depressive symptoms overall, but donors had more symptoms than non-donors (3.5 vs 2.4, P < .001). After risk adjustment, non-donors had significantly less depressive symptoms by PHQ-8 (28% lower, P < .001), but had lower life satisfaction (1.2 points lower, P < .001). CONCLUSIONS: Donors and non-donors have high global levels of overall life satisfaction and low levels of depressive symptoms at 8 weeks after donation or denial. While small effect sizes were observed between groups in these outcomes, being a non-donor was an independent risk factor for lower life satisfaction, which warrants further evaluation.

Best practices to optimize utilization of the National Living Donor Assistance Center for the financial assistance of living organ donors.

Living organ donors face direct costs when donating an organ, including transportation, lodging, meals, and lost wages. For those most in need, the National Living Donor Assistance Center (NLDAC) provides reimbursement to defray travel and subsistence costs associated with living donor evaluation, surgery, and follow-up. While this program currently supports 9% of all US living donors, there is tremendous variability in its utilization across US transplant centers, which may limit patient access to living donor transplantation. Based on feedback from the transplant community, NLDAC convened a Best Practices Workshop on August 2, 2018, in Arlington, VA, to identify strategies to optimize transplant program utilization of this valuable resource. Attendees included team members from transplant centers that are high NLDAC users; the NLDAC program team; and Advisory Group members. After a robust review of NLDAC data and engagement in group discussions, the workgroup identified concrete best practices for administrative and transplant center leadership involvement; for individuals filing NLDAC applications at transplant centers; and to improve patient education about potential financial barriers to living organ donation. Multiple opportunities were identified for intervention to increase transplant programs' NLDAC utilization and reduce financial burdens inhibiting expansion of living donor transplantation in the United States.

Clinically Evident Portal Hypertension: An Operational Research Definition for Future Investigations in the Pediatric Population.

Portal hypertension (PHT) is a major cause of morbidity and mortality in pediatric liver diseases. Thus, research into causes and disease modifiers in PHT in these conditions is vitally important. PHT is rarely directly or indirectly measured in the assessment of children with chronic liver disease. A straightforward, reproducible definition of PHT could be invaluable for consistently identifying patients with PHT and for grouping these patients according to their risk of complications from their disease. We propose the term Clinically Evident Portal Hypertension (CEPH) to denote clinical findings that demonstrate evidence of elevated portal pressure. When CEPH criteria are met, PHT is highly likely to be present, although it is likely that PHT exists for variable periods of time before meeting CEPH criteria. Use of this research definition of CEPH will allow for consistent identification of these patients by clinicians in nearly any clinical setting and serve as a clinical milepost that may dictate future prognosis in pediatric patients with cirrhosis.

Bone Density in Children With Chronic Liver Disease Correlates With Growth and Cholestasis.

Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual-energy X-ray absorptiometry (DXA) analysis was performed in children with intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha-1 antitrypsin deficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height-adjusted and weight-adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height-adjusted and weight-adjusted subtotal BMC Z scores were lower in ALGS participants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.

Kidney transplant graft outcomes in 379 257 recipients on 3 continents.

Kidney transplant outcomes that vary by program or geopolitical unit may result from variability in practice patterns or health care delivery systems. In this collaborative study, we compared kidney graft outcomes among 4 countries (United States, United Kingdom, Australia, and New Zealand) on 3 continents. We analyzed transplant and follow-up registry data from 1988-2014 for 379 257 recipients of first kidney-only transplants using Cox regression. Compared to the United States, 1-year adjusted graft failure risk was significantly higher in the United Kingdom (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.18-1.26, P < .001) and New Zealand (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.14-1.46, P < .001), but lower in Australia (HR 0.90, 95% CI 0.84-0.96, P = .001). In contrast, long-term adjusted graft failure risk (conditional on 1-year function) was significantly higher in the United States compared to Australia, New Zealand, and the United Kingdom (HR 0.74, 0.75, and 0.74, respectively; each P < .001). Thus long-term kidney graft outcomes are approximately 25% worse in the United States than in 3 other countries with well-developed kidney transplant systems. Case mix differences and residual confounding from unmeasured factors were found to be unlikely explanations. These findings suggest that identification of potentially modifiable country-specific differences in care delivery and/or practice patterns should be sought.

Estimating the effect of a rare time-dependent treatment on the recurrent event rate.

In many observational studies, the objective is to estimate the effect of treatment or state-change on the recurrent event rate. If treatment is assigned after the start of follow-up, traditional methods (eg, adjustment for baseline-only covariates or fully conditional adjustment for time-dependent covariates) may give biased results. We propose a two-stage modeling approach using the method of sequential stratification to accurately estimate the effect of a time-dependent treatment on the recurrent event rate. At the first stage, we estimate the pretreatment recurrent event trajectory using a proportional rates model censored at the time of treatment. Prognostic scores are estimated from the linear predictor of this model and used to match treated patients to as yet untreated controls based on prognostic score at the time of treatment for the index patient. The final model is stratified on matched sets and compares the posttreatment recurrent event rate to the recurrent event rate of the matched controls. We demonstrate through simulation that bias due to dependent censoring is negligible, provided the treatment frequency is low, and we investigate a threshold at which correction for dependent censoring is needed. The method is applied to liver transplant (LT), where we estimate the effect of development of post-LT End Stage Renal Disease (ESRD) on rate of days hospitalized.

Biliary reconstructive techniques and associated anatomic variants in adult living donor liver transplantations: The adult-to-adult living donor liver transplantation cohort study experience.

Living donor liver transplantation (LDLT) is a technically demanding endeavor, requiring command of the complex anatomy of partial liver grafts. We examined the influence of anatomic variation and reconstruction techniques on surgical outcomes and graft survival in the 9-center Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Data from 272 adult LDLT recipients (2011-2015) included details on anatomic characteristics and types of intraoperative biliary reconstruction. Associations were tested between reconstruction technique and complications, which included first biliary complication (BC; leak, stricture, or biloma) and first vascular complication (VC; hepatic artery thrombosis [HAT] or portal vein thrombosis [PVT]). Time to patient death, graft failure, and complications were estimated using Kaplan-Meier curves and tested with log-rank tests. Median posttransplant follow-up was 1.2 years. Associations were found between the type of biliary reconstruction and the incidence of VC (P = 0.03) and BC (P = 0.05). Recipients with Roux-en-Y hepaticojejunostomy had the highest probability of VC. Recipients with biliary reconstruction involving the use of high biliary radicals on the recipient duct had the highest likelihood of developing BC (56% by 1 year) compared with duct-to-duct (42% by 1 year). In conclusion, the varied surgical approaches in the A2ALL centers offer a novel opportunity to compare disparate LDLT approaches. The choice to use higher biliary radicals on the recipient duct for reconstruction was associated with more BC, possibly secondary to devascularization and ischemia. The use of Roux-en-Y biliary reconstruction was associated with VCs (HAT and PVT). These results can be used to guide biliary reconstruction decisions in the setting of anatomic variants and inform further improvements in LDLT reconstructions. Ultimately, this information may contribute to a lower incidence of technical complications after LDLT. Liver Transplantation 23 1519-1530 2017 AASLD.

National assessment of early hospitalization after liver transplantation: Risk factors and association with patient survival.

Hospitalization is known to occur frequently in the first 6 months following liver transplantation (LT). Using a novel data linkage between the Scientific Registry of Transplant Recipients and Centers for Medicare and Medicaid Services, our study has 2 objectives: (1) to determine risk factors for "early" hospitalization (ie, within 6 months of LT); and (2) to quantify the importance of hospitalization history in the first 6 months with respect to subsequent patient survival (ie, survival, conditional on surviving 6 months post-LT). The study population consisted of patients aged ≥18 years who underwent deceased donor LT between January 1, 2003 and December 31, 2010, with Medicare as primary or secondary insurance and were discharged alive from the index LT hospitalization (n = 7220). The early hospitalization rate was 2.76 per patient-year and was significantly associated with many recipient factors (eg, recipient age, hepatitis C, diabetes, poor renal function including dialysis, and recipient of transjugular intrahepatic portosystemic shunt procedure before LT), as well as donor race and donation after cardiac death. Conditional on surviving 6 months after LT, the covariate-adjusted death rate increased by 22% for each additional hospitalization occurring in the first 6 months (hazard ratio, 1.22; P < 0.001). In conclusion, several LT recipient factors are significantly associated with early hospitalization. Moreover, a patient's hospitalization profile during follow-up months 0-6 is a very strong predictor of survival thereafter. Efforts and resources should be devoted toward identifying LT recipients at risk for early hospitalization and modifying the actionable risk factors such as hepatitis C, diabetes, and body mass index to improve resource utilization and overall outcomes. Liver Transplantation 23 1143-1152 2017 AASLD.

Hepatic Hemodynamics and Portal Flow Modulation: The A2ALL Experience.

OBJECTIVE: A principal aim of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study was to study hepatic blood flow and effect of portal flow modulation on graft outcomes in the setting of increasing use of smaller and left lobe grafts. METHODS: Recipients of 274 living donor liver transplant were enrolled in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, including 233 (85.0%) right lobes, 40 (14.6%) left lobes, and 1 (0.5%) left lateral section. Hepatic hemodynamics were recorded after reperfusion. A total of 57 portal flow modulations were performed on 52 subjects. RESULTS: Modulation lowered portal pressure in 68% of subjects with inconsistent effects on hepatic arterial and portal flow. A higher rate of graft dysfunction was observed in modulated vs. unmodulated subjects (31% vs. 18%; P = 0.03); however, graft survival in modulated subjects was not different from unmodulated subjects at 3 years. CONCLUSIONS: These results suggest the need for a study using a prespecified portal flow modulation protocol with defined indications to better define the effects of these interventions.

National Assessment of Hospitalization Rates for Incident End-Stage Renal Disease After Liver Transplantation.

BACKGROUND: We examined the association of incident end-stage renal disease (ESRD) after liver transplantation (LT) and resource utilization using a data linkage between the Scientific Registry of Transplant Recipients and claims data from the Centers for Medicare and Medicaid Services. METHODS: The study cohort consisted of patients aged ≥18 years who underwent deceased donor LT between January 1, 2003, and December 31, 2010, with Medicare as primary or secondary insurance and were discharged alive from the index LT hospitalization (n = 7019). The association of ESRD and post-LT hospitalization was assessed by sequential stratification, which entailed prognostic score matching of ESRD-free patients to each LT recipient at ESRD onset. The prognostic score was developed from a model of time to hospitalization and included baseline factors and hospitalization history as predictors. RESULTS: The overall hospitalization rates for LT recipients with and without ESRD were 2.7 and 1.1 per patient-year at risk, respectively. The total number of days hospitalized patient per year was 23 in ESRD and 7 in non-ESRD LT recipients. The adjusted post-LT hospitalization rate was 97% higher after reaching ESRD compared to non-ESRD (hazard ratio, 1.97; P < 0.0001). CONCLUSIONS: Hospitalization rates increased significantly for LT recipients after ESRD onset. Early risk factor modification efforts targeting patients who are at high ESRD risk may reduce post-LT ESRD incidence and hence decrease morbidity and cost among LT recipients.

Recurrent primary sclerosing cholangitis in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study: Comparison of risk factors between living and deceased donor recipients.

Primary sclerosing cholangitis (PSC) recurs in 15%-25% of patients transplanted for PSC. In the United States, PSC transplant patients are more likely to receive an organ from a living donor (LD) than patients without PSC. Our aims were to (1) compare risk of PSC recurrence in LD versus deceased donor recipients and (2) identify risk factors for PSC recurrence. There were 241 living donor liver transplantations (LDLTs) and 65 deceased donor liver transplantation (DDLT) patients transplanted between 1998 and 2013 enrolled in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study who were evaluated. PSC recurrence risk for LDLT and DDLT recipients was compared using Kaplan-Meier survival curves and log-rank tests. Cox models were used to evaluate PSC risk factors. Overall PSC recurrence probabilities were 8.7% and 22.4% at 5 and 10 years after liver transplantation (LT), respectively. The risk of PSC recurrence was not significantly different for DDLT versus LDLT recipients (P = 0.36). For DDLT versus LDLT recipients, unadjusted 5- and 10-year PSC recurrence was 9.4% versus 9.5% and 36.9% versus 21.1%. Higher laboratory Model for End-Stage Liver Disease (MELD) score at LT, onset of a biliary complication, cholangiocarcinoma, and higher donor age were associated with increased risks of PSC recurrence: for MELD (hazard ratio [HR] = 1.06; 95% confidence interval [CI] 1.02-1.10 per MELD point, P = 0.002); for biliary complication (HR, 2.82; 95% CI, 1.28-6.25; P = 0.01); for cholangiocarcinoma (HR, 3.98; 95% CI, 1.43-11.09; P = 0.008); for donor age (per 5-years donor age; HR, 1.17; 95% CI, 1.02-1.35; P = 0.02). Factors not significantly associated with PSC recurrence included the following: first-degree relative donor (P = 0.11), post-LT cytomegalovirus infection (P = 0.38), and acute rejection (P = 0.22). Risk of recurrent PSC was not significantly different for DDLT and LDLT recipients. Biliary complications, cholangiocarcinoma, MELD, and donor age were significantly associated with risk of PSC recurrence. Liver Transplantation 22 1214-1222 2016 AASLD.

Patterns of Early Allograft Dysfunction in Adult Live Donor Liver Transplantation: The A2ALL Experience.

BACKGROUND: Early allograft dysfunction (EAD) after living donor liver transplantation (LDLT) has often been attributed to inadequate graft size, and termed small-for-size syndrome. Early allograft dysfunction definitions include a variable constellation of findings, including hyperbilirubinemia, coagulopathy, encephalopathy, and ascites formation. Among putative causes of EAD after LDLT are excessive portal pressure and/or flow. Our objective was to evaluate patterns of EAD after LDLT. METHODS: In this study, 631 LDLT recipients were monitored for complications, EAD (defined by postoperative day 7 bilirubin >10 mg/dL or international normalized ratio >1.6), and graft failure. Approximately 200 had portal venous and arterial pressure and flow measurements before and after LDLT. Portal inflow modification (splenic artery ligation, hemiportocaval shunt, or splenectomy) was performed at the discretion of the operating surgeon. Associations between EAD and recipient, donor, and transplant factors were examined using multivariable logistic regression. RESULTS: Risk of EAD was associated with left lobe grafts, lower graft weight among left lobes, higher preoperative bilirubin, higher portal reperfusion pressure, higher donor age, and higher donor body mass index. The risk of graft loss within the first 90 days was 5.2 times higher for recipients with EAD versus those without EAD (P < 0.001). CONCLUSIONS: Early allograft dysfunction can be defined using postoperative day 7 laboratory values that are highly predictive of early graft failure within 90 days. Risk factors associated with EAD after LDLT include: graft type and size, preoperative bilirubin, portal reperfusion pressure, donor age, and donor body mass index.

Serum sodium and survival benefit of liver transplantation.

Hyponatremia is associated with elevated wait-list mortality among end-stage liver disease candidates for liver transplantation (LT). However, the effect of low serum sodium on the survival benefit of LT has not been examined. We sought to determine whether pretransplant hyponatremia is associated with an altered LT survival benefit. Data were obtained from the Scientific Registry of Transplant Recipients. The study population consisted of adults (age ≥ 18 years) placed on the waiting list for LT between January 1, 2005 and December 31, 2012 (n = 69,213). The effect of hyponatremia on the survival benefit was assessed via sequential stratification, an extension of Cox regression. Each transplant recipient was matched to appropriate candidates then active on the waiting list with the same Model for End-Stage Liver Disease (MELD) score and in the same donation service area. The focus of the analysis was the interaction between the serum sodium and the MELD score with respect to the survival benefit of LT; this was defined as the covariate-adjusted hazard ratio contrasting post-LT mortality and pre-LT mortality. The LT survival benefit increased significantly with decreasing serum sodium values when the MELD scores were >11. The survival benefit of LT was not affected by serum sodium for patients with MELD scores ≤ 11. In conclusion, the LT survival benefit (or lack thereof) is independent of serum sodium for patients with MELD scores ≤ 11. The increase in the survival benefit with decreasing serum sodium among patients with MELD scores > 11 is consistent with recently approved changes to the allocation system incorporating serum sodium.