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BACKGROUND & AIMS: Liver transplantation for patients with acute-on-chronic liver failure (ACLF) with 3 or more failing organs (ACLF-3) is controversial. We compared liver waitlist mortality or removal according to model for end-stage liver disease (MELD) score vs ACLF category. We also studied factors associated with reduced odds of survival for 1 year after liver transplantation in patients with ACLF-3. METHODS: We analyzed data from the United Network for Organ Sharing (UNOS) from 2005 through 2016. We identified patients who were on the waitlist (100,594) and those who received liver transplants (50,552). Patients with ACLF were identified based on the European Association for the Study of the Liver-chronic liver failure criteria. Outcomes were evaluated with competing risks regression, Kaplan-Meier analysis, and Cox proportional hazards regression. RESULTS: Patients with ACLF-3 were more likely to die or be removed from the waitlist, regardless of MELD-sodium (MELD-Na) score, compared with the other ACLF groups; the proportion was greatest for patients with an ACLF-3 score and MELD-Na score below 25 (43.8% at 28 days). Mechanical ventilation at liver transplantation (hazard ratio [HR] 1.49; 95% confidence interval [CI] 1.22-1.84), donor risk index above 1.7 (HR 1.22; 95% CI 1.09-1.35), and liver transplantation within 30 days of listing (HR 0.89; 95% CI 0.81-0.98) were independently associated with survival for 1 year after liver transplantation CONCLUSIONS: In an analysis of data from the UNOS registry, we found high mortality among patients with ACLF-3 on the liver transplant waitlist, even among those with lower MELD-Na scores. So, certain patients with ACLF-3 have poor outcomes regardless of MELD-Na score. Liver transplantation increases odds of survival for these patients, particularly if performed within 30 days of placement on the waitlist. Mechanical ventilation at liver transplantation and use of marginal organs were associated with increased risk of death.
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Insuficiencia Hepática Crónica Agudizada/cirugía , Trasplante de Hígado , Listas de Espera , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/mortalidad , Adulto , Toma de Decisiones Clínicas , Bases de Datos Factuales , Técnicas de Apoyo para la Decisión , Femenino , Fragilidad/diagnóstico , Fragilidad/mortalidad , Estado de Salud , Humanos , Estado de Ejecución de Karnofsky , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Selección de Paciente , Valor Predictivo de las Pruebas , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Listas de Espera/mortalidadRESUMEN
BACKGROUND: It remains unknown to what extent hepatocellular carcinomas (HCCs) are detected very early (T1 stage; ie, unifocal <2 cm) in the United States. The aim of this study was to investigate the trends and factors associated with very early detection of HCC and resultant outcomes. METHODS: Patients with HCC diagnosed from 2004 through 2014 were identified from the National Cancer Database. Logistic regression was used to identify factors associated with T1 HCC detection, and Cox proportional hazard analyses identified factors associated with overall survival among patients with T1 HCC. RESULTS: Of 110,182 eligible patients, the proportion with T1 HCC increased from 2.6% in 2004 to 6.8% in 2014 (P<.01). The strongest correlate of T1 HCC detection was receipt of care at an academic institution (odds ratio, 3.51; 95% CI, 2.31-5.34). Older age, lack of insurance, high Model for End-Stage Liver Disease (MELD) score, high alpha-fetoprotein, increased Charlson-Deyo comorbidity score, and nonsurgical treatment were associated with increased mortality, and care at an academic center (hazard ratio [HR], 0.27; 95% CI, 0.15-0.48) was associated with reduced mortality in patients with T1 HCC. Liver transplantation (HR, 0.27; 95% CI, 0.20-0.37) and surgical resection (HR, 0.67; 95% CI, 0.48-0.93) were independently associated with improved survival compared with ablation. This is the first study to examine the trend of T1 HCC using the National Cancer Database, which covers approximately 70% of all cancer diagnoses in the United States, using robust statistical analyses. Limitations of the study include a retrospective study design using administrative data and some pertinent data that were not available. CONCLUSIONS: Despite increases over time, <10% of HCCs are detected at T1 stage. The strongest correlates of survival among patients with T1 HCC are receiving care at an academic institution and surgical treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/terapia , Enfermedad Hepática en Estado Terminal , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/terapia , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVES: Chronic infection with hepatitis C virus (HCV) was previously the leading indication for liver transplant (LT) in the United States. However, since 2014 the use of direct-acting antivirals (DAAs) has decreased the chronic HCV burden, while the prevalence of nonalcoholic steatohepatitis (NASH) has risen substantially through the last decade. Both gender and ethnic disparities in indications for LT have been shown in the past but no data on this have been reported since the implementation of DAAs. METHODS: We assessed changes in etiologies for LT listing and in gender and ethnic differences in those listed for LT. Adult patients registered for LT in the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between January 1, 2004 and December 31, 2016 were included. Multinomial logistic regression modeling was used to test for changes in waitlist or liver transplant rates. RESULTS: The study included 127,164 adult patients registered for LT. By 2016, alcoholic liver disease (ALD) was the leading etiology for waitlisting and LT; NASH was second; hepatocellular carcinoma (HCC) due to chronic HCV and chronic HCV alone were 3rd and 4th. NASH was the leading cause for LT for women and the 2nd leading cause for men (following ALD). NASH increased as the cause in all ethnic subgroups and was the leading cause in 2016 among Asian, Hispanic, and non-Hispanic white females. We also found that although the indication for liver transplant for hepatocellular carcinoma (HCC) due to HCV has increased over the years, this indication decreased for the first time between 2015 and 2016 in both males and females. CONCLUSIONS: NASH is currently the second leading cause for LT waitlist registration/liver transplantation overall, and in females, the leading cause. Given the rate of increase, NASH will likely rise to become the leading indication for LT in males as well.
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Etnicidad/estadística & datos numéricos , Disparidades en Atención de Salud/etnología , Trasplante de Hígado/tendencias , Enfermedad del Hígado Graso no Alcohólico/cirugía , Listas de Espera , Adulto , Anciano , Antivirales/uso terapéutico , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/cirugía , Estudios de Cohortes , Bases de Datos Factuales/estadística & datos numéricos , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/cirugía , Humanos , Hepatopatías Alcohólicas/epidemiología , Hepatopatías Alcohólicas/cirugía , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Prevalencia , Factores de Riesgo , Factores Sexuales , Estados Unidos/epidemiologíaRESUMEN
Alcoholic hepatitis (AH) is a condition of acute liver inflammation in the setting of heavy alcohol use that is often managed with corticosteroids in severe cases. Among non-responders to steroids, however, prognosis is poor with up to 75% mortality within 6 months after treatment failure. Early liver transplantation (LT) can achieve an acceptable short-term survival, and initial studies have demonstrated 3-year survival rates of up to 84%. However, the practice of early LT in severe AH remains controversial with concerns over the 6-month rule of sobriety and risk of alcohol relapse post-transplant. Proponents of LT advocate for better understanding of alcohol use as a disorder rather than self-inflicted cause of illness, aim to redefine the misguided application of the 6-month rule, and point out similar relapse rates among patients with early LT and those with greater than 6 months abstinence before transplant. Opponents of LT emphasize the correlation between alcohol relapse and graft failure and mortality, public resistance and potential for distrust among donors, and arguments that transplant centers need to establish improved models to predict relapse and standardize candidate selection criteria across centers. Here we review recent literature on this controversy and provide recommendations for moving forward to consensus.
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Hepatitis Alcohólica/cirugía , Trasplante de Hígado , Abstinencia de Alcohol , Toma de Decisiones Clínicas , Técnicas de Apoyo para la Decisión , Supervivencia de Injerto , Hepatitis Alcohólica/diagnóstico , Hepatitis Alcohólica/mortalidad , Humanos , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Selección de Paciente , Complicaciones Posoperatorias/etiología , Recurrencia , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
The Braden Scale is a standardized tool to assess pressure ulcer risk that is reported for all hospitalized patients in the United States per requirements of the Center for Medicare and Medicaid Services. Previous data have shown the Braden Scale can predict both frailty and mortality risk in patients with decompensated cirrhosis. Our aim was to evaluate the association of the Braden Scale score with short-term outcomes after liver transplantation (LT). We performed a retrospective cohort study of deceased donor LT recipients at 2 centers and categorized them according to the Braden Scale at hospital admission as low (>18), moderate (16-18), or high risk (<16) for pressure ulcer. We created logistic and Poisson multiple regression models to evaluate the association of Braden Scale category with in-hospital and 90-day mortality, length of stay (LOS), nonambulatory status at discharge, and discharge to a rehabilitation facility. Of 341 patients studied, 213 (62.5%) were low risk, 59 (17.3%) were moderate risk, and 69 (20.2%) were high risk. Moderate- and high-risk patients had a greater likelihood for prolonged LOS, nonambulatory status, and discharge to a rehabilitation facility, as compared with low-risk patients. High-risk patients additionally had increased risk for in-hospital and 90-day mortality after LT. Multiple regression modeling demonstrated that high-risk Braden Scale score was associated with prolonged LOS (IRR, 1.56; 95% confidence interval [CI], 1.47-1.65), nonambulatory status at discharge (odds ratio [OR], 4.15; 95% CI, 1.77-9.71), and discharge to a rehabilitation facility (OR, 5.51; 95% CI, 2.57-11.80). In conclusion, the Braden Scale, which is currently assessed in all hospitalized patients in the United States, independently predicted early disability-related outcomes and greater LOS after LT. Liver Transplantation 23 1153-1160 2017 AASLD.
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Enfermedad Hepática en Estado Terminal/cirugía , Anciano Frágil/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Trasplante de Hígado/efectos adversos , Alta del Paciente/estadística & datos numéricos , Úlcera por Presión/epidemiología , Adulto , Anciano , Enfermedad Hepática en Estado Terminal/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Pronóstico , Centros de Rehabilitación/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Donor liver biopsy (DLBx) in liver transplantation provides information on allograft quality; however, predicting outcomes from these allografts remains difficult. METHODS: Between 2006 and 2015, 16 691 transplants with DLBx were identified from the Standard Transplant Analysis and Research database. Cox proportional hazard regression analyses identified donor and recipient characteristics associated with 30-d, 90-d, 1-y, and 3-y graft survival. A composite model, the Liver Transplant After Biopsy (LTAB) score, was created. The Mini-LTAB was then derived consisting of only donor age, macrosteatosis on DLBx, recipient model for end-stage liver disease score, and cold ischemic time. Risk groups were identified for each score and graft survival was evaluated. P values <0.05 were considered significant. RESULTS: The LTAB model used 14 variables and 5 risk groups and identified low-, mild-, moderate-, high-, and severe-risk groups. Compared with moderate-risk recipients, severe-risk recipients had increased risk of graft loss at 30 d (hazard ratio, 3.270; 95% confidence interval, 2.568-4.120) and at 1 y (2.258; 1.928-2.544). The Mini-LTAB model identified low-, moderate-, and high-risk groups. Graft survival in Mini-LTAB high-risk transplants was significantly lower than moderate- or low-risk transplants at all time points. CONCLUSIONS: The LTAB and Mini-LTAB scores represent guiding principles and provide clinically useful tools for the successful selection and utilization of marginal allografts in liver transplantation.
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BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is rarely curable. However, in view of the advent of new treatments, it is critical that patients at high risk for recurrence are identified. METHODS: Patients undergoing LT for HCC at a single centre between 2002 and 2010 were reviewed and data on clinical parameters and explant pathology were analysed to determine factors associated with HCC recurrence. All necrotic and viable tumour nodules were included in explant staging. All patients underwent LT according to the United Network for Organ Sharing (UNOS) Model for End-stage Liver Disease (MELD) tumour exception policies. RESULTS: Liver transplantation was performed in 122 patients with HCC during this period. Rates of recurrence-free survival in the entire cohort at 1 year and 3 years were 95% and 89%, respectively. Thirteen patients developed HCC recurrence at a median of 14 months post-LT. In univariate analysis the factors associated with HCC recurrence were bilobar tumours, vascular invasion, and stage exceeding either Milan or University of California San Francisco (UCSF) Criteria. Multivariate analysis showed pathology outside UCSF Criteria was the major predictor of recurrence; when pathology outside UCSF Criteria was found in combination with vascular invasion, the predicted 3-year recurrence-free survival was only 26%. CONCLUSIONS: Explant pathology can be used to predict the risk for recurrent HCC after LT, which may allow for improved adjuvant and management strategies.
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Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/efectos adversos , Anciano , Carcinoma Hepatocelular/patología , Supervivencia sin Enfermedad , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/patología , Los Angeles , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Uncertainties exist surrounding the timing of liver transplantation (LT) among patients with acute-on-chronic liver failure grade 3 (ACLF-3), regarding whether to accept a marginal quality donor organ to allow for earlier LT or wait for either an optimal organ offer or improvement in the number of organ failures, in order to increase post-LT survival. METHODS: We created a Markov decision process model to determine the optimal timing of LT among patients with ACLF-3 within 7 days of listing, to maximize overall 1-year survival probability. RESULTS: We analyzed 6 groups of candidates with ACLF-3: patients age ≤60 or >60 years, patients with 3 organ failures alone or 4-6 organ failures, and hepatic or extrahepatic ACLF-3. Among all groups, LT yielded significantly greater overall survival probability vs. remaining on the waiting list for even 1 additional day (p <0.001), regardless of organ quality. Creation of 2-way sensitivity analyses, with variation in the probability of receiving an optimal organ and expected post-transplant mortality, indicated that overall survival is maximized by earlier LT, particularly among candidates >60 years old or with 4-6 organ failures. The probability of improvement from ACLF-3 to ACLF-2 does not influence these recommendations, as the likelihood of organ recovery was less than 10%. CONCLUSION: During the first week after listing for patients with ACLF-3, earlier LT in general is favored over waiting for an optimal quality donor organ or for recovery of organ failures, with the understanding that the analysis is limited to consideration of only these 3 variables. LAY SUMMARY: In the setting of grade 3 acute-on-chronic liver failure (ACLF-3), questions remain regarding the timing of transplantation in terms of whether to proceed with liver transplantation with a marginal donor organ or to wait for an optimal liver, and whether to transplant a patient with ACLF-3 or wait until improvement to ACLF-2. In this study, we used a Markov decision process model to demonstrate that earlier transplantation of patients listed with ACLF-3 maximizes overall survival, as opposed to waiting for an optimal donor organ or for improvement in the number of organ failures.
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BACKGROUND: Historically, liver allografts with >30% macrosteatosis (MaS) on donor biopsy have been associated with early allograft dysfunction and worse graft survival; however, successful outcomes have been reported in small cohorts. This study proposes an elevated MaS threshold for organ utilization without detriment to graft survival. METHODS: The UNOS Standard Transplant Analysis and Research database was evaluated for transplants between 2006-2015. Graft survival up to 1-year was evaluated by Kaplan-Meier (KM) survival analyses, and by univariate and multivariable logistic regression analyses, including donor and recipient characteristics. Odds ratios (OR) with 95% confidence intervals (CI) for risk of graft loss are reported. RESULTS: Thirty-day risk of graft loss was increased with MaS as low as 10-19% (OR [95% CI] 1.301 [1.055-1.605], p<0.0001) and peaked with MaS 50-59% (2.921 [1.672-5.103]). At 1-year, risk of graft loss remained elevated with MaS 40-49% (1.465 [1.002-2.142]) and MaS 50-59% (1.978 [1.281-3.056], p = 0.0224). Multivariable models were created for Lower and Higher MELD recipients and MaS cutoffs were established. In Lower MELD recipients, organs with ≥50% MaS had increased risk of graft loss at 30 days (2.451 [1.541-3.897], p = 0.0008) and 1-year post-transplant (1.720 [1.224-2.418], p = 0.0125). Higher MELD recipients had increased risk of graft loss at 30 days with allografts showing MaS ≥40% (4.204 [1.440-5.076], p = 0.0016). At 1-year the risk remained increased, but MaS was not significant predictor of graft loss.048 [1.131-3.710], p = 0.0616). In both MELD cohorts, organs with MaS levels below threshold had similar survival to those transplanted without a donor biopsy. CONCLUSIONS: In conjunction with recipient selection, organs with MaS up to 50% may be safely used without detriment to outcomes.
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Aloinjertos/cirugía , Supervivencia de Injerto/fisiología , Trasplante de Hígado/mortalidad , Adulto , Bases de Datos Factuales , Selección de Donante/métodos , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Estudios Retrospectivos , Factores de Riesgo , Donantes de Tejidos , Trasplante Homólogo/mortalidad , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Mortality for patients with acute-on-chronic liver failure (ACLF) may be underestimated by the model for end-stage liver disease-sodium (MELD-Na) score. AIM: To assess waitlist outcomes across varying grades of ACLF among a cohort of patients listed with a MELD-Na score ≥35, and therefore having similar priority for liver transplantation. METHODS: We analysed the United Network for Organ Sharing (UNOS) database, years 2010-2017. Waitlist outcomes were evaluated using Fine and Gray's competing risks regression. RESULTS: We identified 6342 candidates at listing with a MELD-Na score ≥35, of whom 3122 had ACLF-3. Extra-hepatic organ failures were present primarily in patients with four to six organ failures. Competing risks regression revealed that candidates listed with ACLF-3 had a significantly higher risk for 90-day waitlist mortality (Sub-hazard ratio (SHR) = 1.41; 95% confidence interval [CI] 1.12-1.78) relative to patients with lower ACLF grades. Subgroup analysis of ACLF-3 revealed that both the presence of three organ failures (SHR = 1.40, 95% CI 1.20-1.63) or four to six organ failures at listing (SHR = 3.01; 95% CI 2.54-3.58) was associated with increased waitlist mortality. Candidates with four to six organ failures also had the lowest likelihood of receiving liver transplantation (SHR = 0.61, 95% CI 0.54-0.68). The Share 35 rule was associated with reduced 90-day waitlist mortality among the full cohort of patients listed with ACLF-3 and MELD-Na score ≥35 (SHR = 0.59; 95% CI 0.49-0.70). However, Share 35 rule implementation was not associated with reduced waitlist mortality among patients with four to six organ failures (SHR = 0.76; 95% CI 0.58-1.02). CONCLUSIONS: The MELD-Na score disadvantages patients with ACLF-3, both with and without extra-hepatic organ failures. Incorporation of organ failures into allocation policy warrants further exploration.
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Insuficiencia Hepática Crónica Agudizada/mortalidad , Trasplante de Hígado , Índice de Severidad de la Enfermedad , Listas de Espera , Adulto , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Políticas , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Changing opinions on the alcohol abstinence requirement have led to increased liver transplantation (LT) for alcoholic hepatitis (AH). We aimed to determine the trend in LT for AH in the United States and overall and graft survival rates. METHODS: Adult liver-alone and liver-kidney registrations added to the Organ Procurement and Transplantation Network waiting list between 2004 and 2018 were divided into 3 periods (2004-2009, 2010-2013, 2014-2018). Kaplan-Meier survival models illustrated patient and graft survival. RESULTS: Between 2004 and 2018, 529 AH patients were registered for and 254 received LT. By periods, 116, 73, and 340 patients were registered for and 49, 17, and 188 patients received LT, respectively, indicating a increase in LT for AH from 2014 to 2018. Yearly registrants from 2014 to 2018 were 32, 47, 51, 70, and 140, and recipients were 16, 24, 24, 38, and 88, respectively, indicating increases of 338% and 450% in registrants and recipients, respectively, since 2014. AH patients had the highest 1- and 3-year posttransplant survival (93.2% and 87.3%, respectively) and graft survival (90.4% and 84.8%, respectively) comparing to other LT recipients. CONCLUSIONS: LT for AH in the United States is at an all-time high with an increased overall patient and graft survival.
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BACKGROUND: Obesity, defined as a high body mass index (hBMI) of 30 kg/m or greater, is a growing epidemic worldwide and is associated with multiple comorbidities. High BMI individuals account for an increasing portion of potential liver donors. Here we evaluate trends in the utilization and outcomes of hBMI donors on a national and regional level and the potential role of liver biopsy in donor evaluation. METHODS: United Network for Organ Sharing Standard Transplant Analysis and Research database was evaluated for deceased donor liver transplants between 2006 and 2016 across 11 Organ Procurement and Transplantation Network regions. High BMI donors were compared with lower BMI counterparts and evaluated for biopsy rates, utilization rates and allograft outcomes. Univariate and multivariable analyses were performed. RESULTS: Seventy-seven thousand fifty potential donors were identified and 60 200 transplants were evaluated. Utilization rates for hBMI donors were 66.1% versus 78.1% for lower BMI donors (P < 0.001). Pretransplant biopsy was performed more frequently in hBMI donors (52.1% vs 33.1%, P < 0.001) and macrosteatosis of 30% or greater was identified more often (21.1% vs 12.2%, P < 0.001). Biopsy performance increased utilization rate of hBMI donors in 7 of 11 Organ Procurement and Transplantation Network regions. region 6 showed the highest rate of biopsy performance, high rate of hBMI donor utilization, and highest 5-year estimated graft survival rates of all regions. CONCLUSIONS: High BMI donors have not previously been associated with worse graft survival in multivariable analyses; however, they are used much less frequently. Liver biopsy may increase the utilization rate of hBMI donors and improve donor selection. Further evaluation of regions with high rates of utilization and good outcomes is warranted.
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Índice de Masa Corporal , Selección de Donante/tendencias , Hígado Graso/patología , Disparidades en Atención de Salud/tendencias , Trasplante de Hígado/tendencias , Obesidad/diagnóstico , Donantes de Tejidos/provisión & distribución , Aloinjertos , Biopsia/tendencias , Bases de Datos Factuales , Hígado Graso/epidemiología , Supervivencia de Injerto , Humanos , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/métodos , Obesidad/epidemiología , Valor Predictivo de las Pruebas , Prevalencia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The Share 35 policy for liver allocation prioritizes patients with Model for End-Stage Liver Disease (MELD) scores ≥ 35 for regional sharing of liver allografts. To better assess donor-recipient interactions and inform expectations, this study identified factors affecting graft survival independent of MELD score and derived a risk index for transplantation in the MELD ≥ 35 population. STUDY DESIGN: The United Network for Organ Sharing (UNOS) STAR database was evaluated for deceased donor liver transplants with recipients' MELD ≥ 35, between January 2006 and June 2016. Data were randomly split into test and validate cohorts. Four individual models of graft survival spanning 90 days to 5 years were evaluated with univariate and multivariate Cox proportional hazards analyses against donor- and recipient-specific characteristics. Significant factors were compiled to generate the Liver Transplant Survival Index (LTSI-35), and survival analyses were performed. RESULTS: Five risk groups (very low, low, moderate, high, and severe) were identified, with 1-year graft survival rates of 90.8% ± 0.2%, 89.3% ± 0.3%, 85.0% ± 0.3%, 79.8% ± 0.3%, and 70.3% ± 0.4% (p < 0.001 across groups), respectively. The greatest risk of graft loss was associated with donation after circulatory death (DCD) donors (1-year hazard ratio [HR] = 1.61 [95% CI 1.26 to 2.05], p = 0.001), recipients' requiring ventilator support (HR 1.32 [95% CI 1.17 to 1.51], p < 0.001), and recipient portal vein thrombosis (HR 1.21 [95% CI 1.03 to 1.42], p = 0.003). Subgroup analysis revealed increased risk of graft loss with graft macrosteatosis ≥ 30% on pre-donation biopsy at 90 days (HR 1.64 [1.33 to 1.99], p < 0.001). CONCLUSIONS: The LTSI-35 identifies risk factors for graft loss in a high-MELD population which, when combined, may portend worse outcomes. The LTSI-35 may be used to influence donor selection, organ allocation, and to inform expectations for allograft survival.
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Enfermedad Hepática en Estado Terminal/cirugía , Supervivencia de Injerto , Trasplante de Hígado , Índice de Severidad de la Enfermedad , Adulto , Selección de Donante , Femenino , Estudios de Seguimiento , Asignación de Recursos para la Atención de Salud , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Ajuste de Riesgo , Medición de Riesgo , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
This study investigated the genetic composition and the functional implication of CD44 species expressed by intragraft fibroblasts. An LEW-to-F344 heart transplant model of chronic rejection was used. Intragraft fibroblasts recovered from the chronically rejecting allografts displayed a 4.5-fold increase in expression of CD44 mRNA when compared with that of the fibroblasts isolated from non-rejecting heart allografts (P < 0.01). The intragraft fibroblasts preferentially expressed CD44 variant isoforms containing v1 exon transcript. Automated nucleotide sequence analysis revealed that the majority (90.12%) of the CD44 v1 isoforms expressed by the rejecting graft fibroblasts were encoded by a mutated CD44 mRNA, which contained two point mutations and a codon deletion in the v1 coding region. Histochemistry demonstrated a massive deposition of extracellular HA in the rejecting heart allografts. Hyaluronic acid (HA) was able to promote in vitro fibroblast adhesion, migration in a CD44-dependent manner, and survival in a serum-free culture condition. The study concludes that up-regulation of CD44 v1 isoforms expressed by the intragraft fibroblasts is associated with an increase in the deposition of extracellular HA, the principal ligand for CD44, in the allografts, suggesting that CD44-HA interaction plays an important role in regulating fibroblast recruitment and growth in allografts developing chronic rejection.
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Fibroblastos/fisiología , Trasplante de Corazón , Receptores de Hialuranos/genética , Isoformas de Proteínas/genética , Trasplante Homólogo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Adhesión Celular , Movimiento Celular , Supervivencia Celular , Células Cultivadas , Medios de Cultivo Condicionados , Femenino , Fibroblastos/citología , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Trasplante de Corazón/inmunología , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/metabolismo , Masculino , Datos de Secuencia Molecular , Isoformas de Proteínas/metabolismo , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Alineación de Secuencia , Trasplante Homólogo/inmunologíaRESUMEN
BACKGROUND: B cell depletion by anti-CD20 antibody is used in desensitization protocols and for treatment of antibody-mediated rejection (AMR). However, little is known about the efficacy and the mechanism(s) of action. METHODS: A mouse model of HLA sensitization was used to study the effectiveness of anti-CD20 treatment on B cell depletion and anti-HLA antibody suppression. RESULTS: Immunization of C57BL/6 mice with skin grafts from a transgenic C57BL.Tg/HLA-A2.1 mouse resulted in robust production of anti-HLA IgM and IgG antibodies, and accelerated rejection of a secondary skin allograft (within 3 days) featured by intragraft IgG and C4d deposition. Both IgM and IgG alloantibodies are specific to HLA-A2 as well as to a panel of class I HLA, including A1, A3, A25, A26, A29, and A30. These alloantibodies were complement-dependently cytotoxic (CDC) against HLA-A2 expressing target cells. Administration of 2 doses of a mouse-anti-mouse CD20 monoclonal antibody significantly reduced the levels of anti-HLA IgG2a antibodies, suppressed serum CDC, and prolonged survival of the secondary skin allografts. Suppression of anti-HLA IgG antibodies was associated with significant depletion of B220(+)/CD5(-) B cells from the blood, the spleen and the bone marrow of the treated animals. CONCLUSION: Anti-CD20 treatment effectively depletes B220(+)/CD5(-) B cells, resulting in potent suppression of anti-HLA IgG and prolongation of skin graft survival. The data are in support for the use of anti-CD20 antibodies in highly-HLA sensitized patients undergoing desensitization and for the treatment of AMR.
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Anticuerpos Monoclonales/administración & dosificación , Formación de Anticuerpos/efectos de los fármacos , Antígenos CD20/inmunología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/inmunología , Antígeno HLA-A2/genética , Antígeno HLA-A2/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Citotoxicidad Inmunológica , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Humanos , Inmunización Pasiva , Inmunoglobulinas/sangre , Isoanticuerpos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Trasplante de Piel/inmunologíaRESUMEN
BACKGROUND: Ibrutinib is a Bruton's tyrosine Kinase (BTK) antagonist that inhibits B cell receptor (BCR) signaling. Complete BTK deficiency is associated with absence of B-cells. Ibrutinb is currently approved by FDA for treatment of B-cell malignancies, including Waldenström macroglobulinaemia. We recently carried out studies to determine if ibrutinib could modify alloantibody responses. MATERIALS AND METHODS: A mouse model of allogenic sensitization using a C57BL/6 mouse as the recipient of a skin allograft from an HLA-A2 transgenic mouse was utilized to examine the effects of ibrutinib on alloantibody responses and B cell effector functions. Donor-specific antibody (DSA) levels were measured in a flow-cytometric antibody binding assay. Splenic T and B cell subsets and plasma cells were analyzed in flow cytometry. RESULTS: Control mice developed peak levels of DSA IgM at day 14 PTx while the ibrutinib treated mice had significantly lower levels of DSA IgM (p=0.0047). Control mice developed HLA.A2-specific IgG antibodies at day 14 (230±60 MFI) and reached peak levels at day 21 (426±61 MFI). In contrast, mice in the treatment group had low levels of HLA.A2-specific IgG at day 14 (109±59 MFI, p=0.004) and day 21 (241±86 MFI, p=0.003). FACS analysis found a reduction of B220+ or CD19+ B cell population (p<0.05). In addition, ibrutinib attenuated recall DSA IgG responses to re-sensitization (p<0.05) and reduced CD38+CD138+ plasma cells (p<0.05) in the spleens. CONCLUSIONS: Ibrutinib is effective in suppressing alloantibody responses through blocking BTK-mediated BCR signaling, leading to reduction of B cells and short-lived plasma cells in the spleens. Use of ibrutinib may provide benefits to HLA-sensitized transplant patients for alloantibody suppression.
Asunto(s)
Subgrupos de Linfocitos B/fisiología , Linfocitos B/fisiología , Inmunosupresores/uso terapéutico , Células Plasmáticas/fisiología , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adenina/análogos & derivados , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Antígeno HLA-A2/metabolismo , Humanos , Inmunización , Isoanticuerpos/inmunología , Isoantígenos/inmunología , Ratones , Ratones Endogámicos C57BL , PiperidinasRESUMEN
The number of candidates awaiting liver transplantation continues to exceed the available donor organ pool. This steadily increasing donor organ shortage calls for the widening of selection criteria for potential donor organs. Strategies to increase the number of liver allografts include liver splitting, use of donors over 70 years, use of steatotic donor livers, and reutilization of liver allografts after brain death of the first recipient. We report the successful use of a polycystic donor liver and review the experience with this donor population. We propose that the selective use of polycystic donor livers containing small (<5 cm) cysts with preserved liver parenchyma is safe and appropriate.
Asunto(s)
Quistes/patología , Hepatopatías/patología , Trasplante de Hígado/métodos , Trasplante de Hígado/patología , Cadáver , Quistes/genética , Supervivencia de Injerto , Humanos , Hepatopatías/genética , Masculino , Persona de Mediana Edad , Donantes de Tejidos , Obtención de Tejidos y ÓrganosRESUMEN
BACKGROUND: Because of the critical worldwide shortage of cadaveric organ donors, transplant professionals have increasingly turned to living donors. Partial hepatectomy for adult living donor liver transplantation has been performed since the late 1990s. Most often, the complications of living donor hepatectomy have been related to the biliary tract, specifically biliary leaks. METHODS: A 54-year-old man underwent donor right hepatectomy for living donor liver transplantation. Three years after liver donation he presented with upper abdominal pain and fullness. Radiographic workup revealed a diaphragmatic hernia of the right hemithorax. RESULTS: After thoracoscopic evaluation of the right hemithorax, diaphragmatic hernia was repaired. Currently the patient remains well several months after the repair with complete resolution of abdominal pain, normal chest X-ray examination demonstrating no recurrence of diaphragmatic hernia, and normal liver functions tests. CONCLUSIONS: Multiple complications of living donor liver transplantation have been described the transplant literature. Diaphragmatic hernia is a formerly-undescribed complication of right donor hepatectomy for transplantation.
Asunto(s)
Hepatectomía/efectos adversos , Hernia Diafragmática/etiología , Trasplante de Hígado , Donadores Vivos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
It is well known that CTLA4Ig inhibits allogenic T-cell activation in transplantation. The immunological features and mechanisms associated with alloantibody suppression by CTLA4Ig, however, are poorly understood. Here, we used a mouse model of allosensitization to evaluate the efficacy of CTLA4Ig (abatacept) in suppression of donor-specific antibody (DSA) during de novo and recall alloantibody responses. We found that abatacept inhibited de novo DSA IgM and IgG responses to HLA-A2 expressing skin grafts. Abatacept administered during primary T cell priming also reduced recall IgG responses induced by re-immunization. Suppression of de novo DSA responses by abatacept is associated with a reduction in splenic expression of the germinal center activation marker GL7 and a reduction of CD4(+)PD1(+)CXCR5(+) follicular T helper (Tfh) subset in splenic lymphocytes detected by flow cytometry. The efficacy of abatacept on recall DSA suppression is moderate. In vitro experiments demonstrated that abatacept inhibited DSA IgG secretion by CD138(+) plasma cells isolated from allograft recipients. Additional experiments using an IgG1 secreting mouse hybridoma cell line showed that abatacept binds to CD80 expressed on these cells with subsequent inhibition of cell proliferation and reduction in IgG ELISpot formation. In conclusion, CTLA4Ig is a potent suppressor of de novo DSA responses and also affects recall responses. The data suggests modification of recall DSA responses is due to a direct suppressive effect on plasma cells.