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1.
J Clin Med ; 12(10)2023 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-37240511

RESUMEN

Primary sclerosing cholangitis (PSC) is characterized by inflammation of the whole bile duct system. Liver transplantation is only approved as a curative treatment when it comes to end-stage liver disease. The aim of our study was to assess morbidity, survival rates and PSC recurrence and the impact of donor characteristics in long-term follow-up. This was an IRB-approved retrospective study. A total of 82 patients were identified who were transplanted between January 2010 and December 2021 for PSC. Among these patients, 76 adult liver transplant PSC patients and their corresponding donors were analyzed. Three pediatric cases and three adult patients with a follow-up within <1 year were excluded from further analysis. Median (range) age was 47 years (18-70) with a median (range) lab-MELD of 16 (7-40). Median (range) ICU and hospital stays were 4.6 days (0-147) and 21 days (1-176), respectively. The majority of patients suffered from Crohn's disease or ulcerative colitis as a concomitant comorbidity (65.8%). The ten-year survival rate was 74.6%. A significantly lower lab-MELD score was identified in patients surviving for > 10 years (15 vs. 22, p = 0.004). Most patients (65%) passed in the first year following transplantation, with primary non-function (PNF), sepsis and arterial thrombosis being the most common causes of death. Donor characteristics did not affect patient survival. Patients with PSC show excellent 10-year survival rates. While the lab-MELD score significantly affected long term outcomes, donor characteristics did not affect survival rates.

2.
Pharmaceutics ; 13(12)2021 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-34959291

RESUMEN

A transcriptome-wide analysis of human liver for demonstrating differences between young and old humans has not yet been performed. However, identifying major age-related alterations in hepatic gene expression may pinpoint ontogenetic shifts with important hepatic and systemic consequences, provide novel pharmacogenetic information, offer clues to efficiently counteract symptoms of old age, and improve the overarching understanding of individual decline. Next-generation sequencing (NGS) data analyzed by the Mann-Whitney nonparametric test and Ensemble Feature Selection (EFS) bioinformatics identified 44 transcripts among 60,617 total and 19,986 protein-encoding transcripts that significantly (p = 0.0003 to 0.0464) and strikingly (EFS score > 0.3:16 transcripts; EFS score > 0.2:28 transcripts) differ between young and old livers. Most of these age-related transcripts were assigned to the categories 'regulome', 'inflammaging', 'regeneration', and 'pharmacogenes'. NGS results were confirmed by quantitative real-time polymerase chain reaction. Our results have important implications for the areas of ontogeny/aging and the age-dependent increase in major liver diseases. Finally, we present a broadly substantiated and testable hypothesis on a genetically governed 'aging cascade', wherein PPP1R10 acts as a putative ontogenetic master regulator, prominently flanked by IGFALS and DUSP1. This transcriptome-wide analysis of human liver offers potential clues towards developing safer and improved therapeutic interventions against major liver diseases and increased insights into key mechanisms underlying aging.

3.
Clin Kidney J ; 12(6): 895-900, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31807305

RESUMEN

BACKGROUND: The number of patients on waiting lists for repeated kidney transplantation has increased. However, retransplanted patients have a greater surgical and immunological risk than first-time kidney recipients. METHODS: We retrospectively analysed all kidney recipients that underwent third, fourth or fifth kidney transplantation (Group 3+) at the University Hospital Essen, Essen, Germany from October 1973 to January 2017. A historical cohort of recipients retransplanted with a second kidney (Group 2) served as the control. Donor and recipient demographic data, cold ischaemia time (CIT), warm ischaemia time, overall operation time and methods, transplantectomy of previous kidney grafts, incidence of surgical and immunological complications as well as patient- and death-censored survival were analysed. RESULTS: We identified 108 recipients transplanted with the third, fourth or fifth renal allograft. Patients with more than one transplantation had significantly higher surgical risk due to atherosclerosis (P = 0.002) and higher immunological risk due to higher panel reactive antibody levels preoperatively (current panel reactive antibody P = 0.004; highest panel reactive antibody value P = 0.0001). Group 3+ patients had more often undergone previous transplant nephrectomy (P = 0.0001). There was a significant difference in CIT (P = 0.009), overall operative time (P = 0.0001) and post-transplantation thrombotic events (P = 0.02). We could not demonstrate any differences in graft and patient survival. CONCLUSION: Third, fourth and fifth transplant recipients are a high-risk patient cohort. Our results suggest that patient survival after more than three renal transplantations is similar to that of second graft recipients. This supports the concept of repeated kidney retransplantations.

4.
Ann Transplant ; 24: 481-488, 2019 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-31417074

RESUMEN

BACKGROUND Adequate microcirculatory perfusion is essential for the provision of oxygen to the liver following transplantation. Data from the Oxygen Persufflation in Liver Transplantation (OPAL) study (ISRCTN00167887) were analyzed from liver transplants performed at a single center to determine the role of factors affecting the hepatic microcirculation and early allograft dysfunction (EAD). MATERIAL AND METHODS Retrospective data from 116 patients from the Oxygen Persufflation as Adjunction in Liver Transplantation (OPAL) study who underwent liver transplantation at a single center were analyzed. Oxygen saturation of hemoglobin (SO2), relative capillary hemoglobin concentration (rHb), relative tissue blood flow (rBF) using laser Doppler flow measurements, and the Oxygen-to-See (O2C) spectrometry were measured and with post-transplant allograft function were analyzed using univariate and multivariate logistic regression statistics. RESULTS Livers donors had a median donor risk index of 1.8. Most liver transplant recipients were men (60.3%), with a median age of 54 years (IQR, 23-68 years). Mean post-transplant 3-month survival was 90.5%. The EAD rate was 22.4%, the median SO2 was 78% (IQR, 29.5-95.8%), the median rHb was 55.6 AU (IQR, 16.8-74.8 AU), and the median rBF was 110.1 AU (IQR, 35.8-406.8 AU). Multivariate logistic regression analysis showed that tissue SO2 (p=0.01), body mass index (BMI) of the transplant recipient (p=0.002), serum alanine transaminase (ALT) of the donor (p=0.02), and portal blood flow (p=0.01) were predictive factors for EAD. CONCLUSIONS Non-invasive investigations of the liver microcirculation and hemoglobin oxygenation were shown to be predictive factors for EAD following liver transplantation.


Asunto(s)
Trasplante de Hígado/métodos , Hígado/irrigación sanguínea , Microcirculación/fisiología , Disfunción Primaria del Injerto/etiología , Adulto , Anciano , Femenino , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Imagen de Perfusión , Medición de Riesgo , Factores de Riesgo , Receptores de Trasplantes , Resultado del Tratamiento , Adulto Joven
5.
Transplant Direct ; 3(11): e224, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29184912

RESUMEN

BACKGROUND: The demand for transplantable organs exceeds donor organ supply. Transplantation of organs from donors with a history of malignancy remains controversial and the transmission of cancer in liver transplant recipients has not been sufficiently examined. METHODS: From 2002 until 2017, 83 livers from donors with a history of malignancy were transplanted at the University Hospital Essen, Germany. Donor and recipient data, type of malignancy, tumor-free interval at organ procurement, and follow-up data were analyzed. RESULTS: Nine different tumor sites (central nervous system [n = 27], genitourinary [n = 24], breast [n = 10], skin [n = 8], colorectal [n = 5], lung [n = 3], hemato-oncological [n = 3], thyroid [n = 2], and larynx [n = 1]) were detected in 83 donors. The majority (58%) of donors had tumor-free intervals of less than 5 years versus 19% of 6 to 10 years versus 23% over 10 years. The risk of tumor transmission from donors was assessed as low in 44 (53%), intermediate in 28 (34%), and high in 11 (13%) cases. During median follow-up of 19.9 (0-155) months, none of the recipients developed donor-transmitted malignancy. CONCLUSIONS: Liver transplantation with organs from donors with a medical history of malignancy is feasible, and the risk of donor-transmitted malignancy appears to be low in this single-center analysis. A careful selection of donors remains mandatory and can expand the donor pool.

6.
Clin Transplant ; 31(3)2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28035688

RESUMEN

This clinical study evaluates end-ischemic hypothermic machine perfusion (eHMP) in expanded criteria donors (ECD) kidneys. eHMP was initiated upon arrival of the kidney in our center and continued until transplantation. Between 11/2011 and 8/2014 eHMP was performed in 66 ECD kidneys for 369 (98-912) minutes after 863 (364-1567) minutes of cold storage (CS). In 49 of 66 cases, the contralateral kidney from the same donor was preserved by static CS only and accepted by another Eurotransplant (ET) center. Five (10.2%) of these kidneys were ultimately judged as "not transplantable" by the accepting center and discarded. After exclusion of early unrelated graft losses, 43 kidney pairs from the same donor were eligible for direct comparison of eHMP vs CS only: primary non-function and delayed graft function (DGF) were 0% vs 9.3% (P=.04) and 11.6% vs 20.9% (P=.24). There was no statistically significant difference in 1-year graft survival (eHMP vs CS only: 97.7% vs 88.4%, P=.089). In a multivariate analysis, eHMP was an independent factor for prevention of DGF (OR: 0.28, P=.041). Development of DGF was the strongest risk factor for 1-year graft failure (Renal resistance: 38.2, P<.001). In summary, eHMP is a promising reconditioning technique to improve the quality and acceptance rate of suboptimal grafts.


Asunto(s)
Rechazo de Injerto/prevención & control , Hipotermia Inducida , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Preservación de Órganos/métodos , Perfusión/instrumentación , Donantes de Tejidos , Adulto , Anciano , Anciano de 80 o más Años , Criopreservación , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/epidemiología , Supervivencia de Injerto , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Obtención de Tejidos y Órganos/métodos
7.
Pediatr Transplant ; 19(8): 858-65, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26341656

RESUMEN

CLKT and sequential KALT are decided on a case-by-case basis in children for special indications such as ARPKD or PH1. We report on 21 children who underwent CLKT or KALT at our hospital between 1998 and 2013. Eleven children were diagnosed with PH1 and six with ARPKD. Other diagnosis were Joubert syndrome (n = 1), nephronophthisis (n = 1), CF (n = 1), and hepatocellular carcinoma (n = 1). Children (12 males, nine females) were aged 7.8 ± 6.2 yr (range, 10 months to 18 yr) at time of transplantation. Average wait time was 1.9 ± 0.9 yr (range, four months to 2.3 yr). Fifteen patients received dialysis prior to transplantation. In PH1 patients, four children received CLKT, five received KALT, and two infants have received only an LTx, whereas all six patients with ARPKD received CLKT. In patients with other indications, CLKT was performed in three cases and KALT in one girl. Cumulative 10-yr survival of all 21 patients was 78.4%. At the time of transfer into adult care, 13 patients retained stable liver and kidney function. Regardless the underlying diagnosis, CLKT and KALT can be performed in children with good surgical outcomes and long-term survival.


Asunto(s)
Hiperoxaluria Primaria/cirugía , Trasplante de Riñón/métodos , Trasplante de Hígado/métodos , Riñón Poliquístico Autosómico Recesivo/cirugía , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Hiperoxaluria Primaria/mortalidad , Lactante , Masculino , Riñón Poliquístico Autosómico Recesivo/mortalidad , Complicaciones Posoperatorias , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento
8.
Pediatr Transplant ; 19(8): 875-9, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26346176

RESUMEN

In LT, the common policy is to allocate pediatric liver grafts to pediatric recipients. Pediatric organs are also offered to adults if there is no pediatric recipient. However, they are rarely accepted for adult recipients. So far, there is no information available reporting outcome of LT in adult recipients using pediatric livers from donors ≤ 6 yr. In this study, we included nine adult recipients (seven females and two males) who received grafts from children ≤ 6 yr from January 2008 to December 2013. We evaluated the graft quality, the GBWR and analyzed the recipients' perioperative course. Laboratory samples and graft perfusion were analyzed. Nine adults with a median age of 49 yr (range: 25-65) and a median weight of 60 kg (range: 48-64) underwent LT with a pediatric donor graft. Median donor age was five yr (range: 3-6). Median GBWR was 1.02 (range: 0.86-1.45). After a median follow-up of 3.9 yr (range: 11 months-6.6 yr), patient survival was 100%; graft survival was 89%. One patient needed re-transplantation on the second postoperative day due to PNF. Eight recipients were discharged from the ICU after 2-9 days with a regular graft function. Doppler scans revealed regular flow patterns at any time. Only if denied for pediatric recipients, the use of pediatric livers from donors ≤ 6 yr for adult recipients is a considerable option.


Asunto(s)
Trasplante de Hígado/métodos , Donantes de Tejidos , Adulto , Factores de Edad , Anciano , Niño , Preescolar , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Humanos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud
9.
Liver Int ; 35(1): 156-63, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24351095

RESUMEN

BACKGROUND & AIMS: Poor initial graft function was recently newly defined as early allograft dysfunction (EAD) [Olthoff KM, Kulik L, Samstein B, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010; 16: 943]. Aim of this analysis was to evaluate predictive donor information for development of EAD. METHODS: Six hundred and seventy-eight consecutive adult patients (mean age 51.6 years; 60.3% men) who received a primary liver transplantation (LT) (09/2003-12/2011) were included. Standard donor data were correlated with EAD and outcome by univariable/multivariable logistic regression and Cox proportional hazards to identify prognostic donor factors after adjustment for recipient confounders. Estimates of relevant factors were utilized for construction of a new continuous risk index to develop EAD. RESULTS: 38.7% patients developed EAD. 30-day survival of grafts with and without EAD was 59.8% and 89.7% (P < 0.0001). 30-day survival of patients with and without EAD was 68.5% and 93.1% (P < 0.0001) respectively. Donor body mass index (P = 0.0112), gGT (P = 0.0471), macrosteatosis (P = 0.0006) and cold ischaemia time (CIT) (P = 0.0031) were predictors of EAD. Internal cross validation showed a high predictive value (c-index = 0.622). CONCLUSIONS: Early allograft dysfunction correlates with early results of LT and can be predicted by donor data only. The newly introduced risk index potentially optimizes individual decisions to accept/decline high risk organs. Outcome of these organs might be improved by shortening CIT.


Asunto(s)
Aloinjertos/fisiopatología , Trasplante de Hígado/efectos adversos , Puntuaciones en la Disfunción de Órganos , Donantes de Tejidos/estadística & datos numéricos , Adulto , Factores de Edad , Bilirrubina/sangre , Índice de Masa Corporal , Femenino , Humanos , Estimación de Kaplan-Meier , Trasplante de Hígado/estadística & datos numéricos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Factores Sexuales
10.
Am Surg ; 80(12): 1230-6, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25513922

RESUMEN

Live donor kidney transplantation (LDKT) with elderly donors is a controversial topic. The purpose of this study was to evaluate donor and recipient outcomes involving live donors 60 years of age or older. All LDKTs performed at our institution from January 2000 to January 2011 were evaluated. Statistical analysis included t test, uni- and multivariate regression analyses, and Kaplan-Meier survival analysis. Forty-seven LDKTs were performed with donors 60 years of age or older. Median donor age was 65 years. Fifty-seven per cent were female. Forty-one recipients received their first KT (seven pre-emptive). Initial graft function was documented in 45 patients (96%). After a median follow-up of 69 months, 1-, 3-, and 5-year graft and patient survival rates were 98, 98, and 95 per cent and 96, 94, and 87 per cent, respectively. Univariate Cox proportional hazard analysis showed donor body mass index and previous KT to be predictors of graft survival. Recipient comorbidity index, HLA-B mismatches, and creatinine level at 2 years post-KT were predictors of patient survival. None of these variables remained significant by multivariate analysis. Female gender was the only positive predictor of donor postoperative creatinine levels. Satisfactory long-term donor and recipient outcomes can be achieved with live kidney donors 60 years of age or older. Careful evaluation and selection remain key to success. The role of female gender in donor long-term kidney function should be further investigated.


Asunto(s)
Trasplante de Riñón/mortalidad , Trasplante de Riñón/métodos , Donadores Vivos , Receptores de Trasplantes/estadística & datos numéricos , Factores de Edad , Anciano , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Estimación de Kaplan-Meier , Trasplante de Riñón/efectos adversos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Factores Sexuales , Estadísticas no Paramétricas , Tasa de Supervivencia
11.
Transpl Int ; 27(12): 1285-93, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25082387

RESUMEN

Perioperative liver graft injury is associated with elevation of aminotransferases after orthotopic liver transplantation (OLT). Values above 5000 U/l usually are regarded as extreme liver graft injury (ELGI). Some patients and organs recover from this critical condition. The aim of the study was to evaluate factors contributing to graft and patient survival after ELGI. From chart review we identified 64 of 917 OLT adult patients (median age 54.2 years; 68.8% males) transplanted between 11/2003 and 02/2012, who presented ELGI after OLT. Donor and recipient factors were analyzed and correlated with the outcome by univariable and multivariable methods. Multivariable cox proportional hazards showed that recipient's BMI (P = 0.01), model for end stage liver disease (MELD) score before OLT (P = 0.02) and laboratory MELD score 24 h after OLT (P = 0.01) were independently associated with patient survival. 30-days and 12-months survival in patients with a postoperative laboratory MELD higher than 31 was 21.4%, while patients with a postoperative laboratory MELD lower than 31 displayed 30-days and 12-months survival rates of 80% and 71.8%, respectively (P < 0.001). Retransplantation in the setting of ELGI after OLT should be based on all available data. Utilization of the postoperative labMELD enables the transplant physician within 24 h after transplantation to identify necessity of retransplantation objectively.


Asunto(s)
Aspartato Aminotransferasas/sangre , Trasplante de Hígado/estadística & datos numéricos , Complicaciones Posoperatorias/sangre , Índice de Severidad de la Enfermedad , Adulto , Anciano , Alanina Transaminasa/sangre , Aloinjertos , Enfermedad Hepática en Estado Terminal/sangre , Femenino , Supervivencia de Injerto , Humanos , Terapia de Inmunosupresión , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/mortalidad , Modelos de Riesgos Proporcionales , Reoperación , Resultado del Tratamiento , Adulto Joven
12.
PLoS One ; 9(7): e102351, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25025159

RESUMEN

BACKGROUND/AIMS: Emerging data links different aspects of lipid metabolism to liver regeneration. In patients with acute liver failure (ALF), low levels of lipids may correlate with disease severity. Thus, we determined whether there is an etiology-specific link between lipid levels in patients suffering from ALF and aimed to investigate an effect of lipid levels on the prognosis of ALF. METHODS: In this retrospective single center study, we reviewed 89 consecutive ALF patients, who met the criteria of the "Acute Liver Failure Study Group". Patient characteristics, clinical data and laboratory parameters were individually analyzed at admission and correlated with the patients' outcome after a four week follow up. Possible endpoints were either discharge, or death or liver transplantation. RESULTS: High-density lipoprotein (HDL), cholesterol and triglyceride levels were significantly lower in patients who died or required a liver transplant. HDL levels were significantly higher in patients with ALF caused by acetaminophen intoxication, compared to fulminant HBV infection or drug induced liver injury. HDL levels correlated with hepatic injury by ALT levels, and Albumin, and inversely correlated with the MELD score, INR, and bilirubin. CONCLUSION: In our cohort of patients with ALF, we could show that HDL and cholesterol are suppressed. In addition novel etiology specific patterns between acteminophen and non-acteminophen induced liver failure were detected for serum lipid components. Further studies are needed to address the role of cholesterol and lipid metabolism and the according pathways in different etiologies of ALF.


Asunto(s)
Lípidos/sangre , Fallo Hepático/etiología , Fallo Hepático/patología , Enfermedad Aguda , Humanos , Fallo Hepático/sangre , Estudios Retrospectivos
13.
Transfusion ; 54(10 Pt 2): 2760-8, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24827116

RESUMEN

BACKGROUND: Allogeneic blood products transfusion during liver transplantation (LT) can be associated with increased morbidity and mortality. Data on thromboelastometry (ROTEM)-guided coagulation management with coagulation factor concentrates (CFCs)-fibrinogen concentrate and/or prothrombin complex concentrate (PCC)-are sparse. We aimed to retrospectively evaluate the safety events observed with this approach in our clinic. STUDY DESIGN AND METHODS: LT patients from January 2009 to December 2010 (n = 266) were identified by chart review. A ROTEM-based algorithm with CFC guided the hemostatic therapy. Doppler ultrasound was used to evaluate thrombosis in the hepatic artery, portal vein, and hepatic veins. Stroke, myocardial ischemia, pulmonary embolism, and transfusion variables were recorded. Patients receiving CFC were included in the CFC group (n = 156); those not receiving CFC were included in the non-CFC group (n = 110). Safety events were compared between these two groups. RESULTS: Allogeneic transfusion(s) in the 266 patients was low, with medians of 2 (interquartile range [IQR], 0-5), 0 (IQR 0-0), and 0 (IQR 0-1) units for red blood cells (RBCs), fresh-frozen plasma (FFP), and platelets (PLTs), respectively. Ninety-seven of 266 LTs (36.5%) were performed without RBCs transfusion, 227 (85.3%) without FFP, and 190 (71.4%) without PLTs. There were no significant differences in thrombotic, thromboembolic, and ischemic adverse events occurrence between the CFC group and the non-CFC group (11/156 patients vs. 5/110; p = 0.31). CONCLUSION: In LT, ROTEM-guided treatment with fibrinogen concentrate and/or PCC did not appear to increase the occurrence of thrombosis and ischemic events compared to patients who did not receive these concentrates.


Asunto(s)
Factores de Coagulación Sanguínea/uso terapéutico , Coagulación Sanguínea , Transfusión de Componentes Sanguíneos/estadística & datos numéricos , Hepatopatías/cirugía , Trasplante de Hígado/estadística & datos numéricos , Tromboelastografía/métodos , Adulto , Algoritmos , Transfusión de Componentes Sanguíneos/efectos adversos , Transfusión de Componentes Sanguíneos/mortalidad , Femenino , Fibrinógeno/uso terapéutico , Humanos , Isquemia/etiología , Isquemia/mortalidad , Hepatopatías/mortalidad , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Trombosis/diagnóstico por imagen , Trombosis/etiología , Trombosis/mortalidad , Reacción a la Transfusión/etiología , Reacción a la Transfusión/mortalidad , Ultrasonografía Doppler
14.
Hepatology ; 58(4): 1362-74, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23703673

RESUMEN

UNLABELLED: Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2). We employed 50 human CCA samples (25 intrahepatic and 25 extrahepatic CCA) as well as human KMCH-1, Mz-CHA-1, and HUCCT-1 CCA cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. In human samples, polo-like kinase (PLK)1/2/3-immunoreactive cancer cells were present in the preponderance of intra- and extrahepatic CCA specimens. Inhibition of Hh signaling by cyclopamine reduced PLK2, but not PLK1 or PLK3, messenger RNA and protein expression in vehicle-treated and sonic Hh-treated CCA cells, confirming our previous microarray study. PLK2 regulation by Hh signaling appears to be direct, because the Hh transcription factors, glioma-associated oncogene 1 and 2, bind to the PLK2 promotor. Moreover, inhibition of PLK2 by the PLK inhibitor, BI 6727 (volasertib), or PLK2 knockdown was proapoptotic in CCA cells. BI 6727 administration or PLK2 knockdown decreased cellular protein levels of antiapoptotic myeloid cell leukemia 1 (Mcl-1), an effect reversed by the proteasome inhibitor, MG-132. Finally, BI 6727 administration reduced Mcl-1 protein expression in CCA cells, resulting in CCA cell apoptosis and tumor suppression in vivo. CONCLUSION: PLK2 appears to be an important mediator of Hh survival signaling. These results suggest PLK inhibitors to be of therapeutic value for treatment of human CCA.


Asunto(s)
Neoplasias de los Conductos Biliares/fisiopatología , Conductos Biliares Intrahepáticos , Colangiocarcinoma/fisiopatología , Proteínas Hedgehog/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Transducción de Señal/fisiología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Supervivencia Celular/fisiología , Colangiocarcinoma/patología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Xenoinjertos , Humanos , Masculino , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Pteridinas/farmacología , Ratas , Ratas Endogámicas F344 , Ligando Inductor de Apoptosis Relacionado con TNF/fisiología
15.
Pediatr Transplant ; 17(2): 179-84, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23442102

RESUMEN

Kidneys from donors ≤5 yr of age represent a controversial issue. The purpose of this study was to compare the transplant outcomes as single and single/en bloc grafts into pediatric and adult KT recipients, respectively. All recipients of kidneys from donors ≤5 yr old transplanted at our institution from 3/2003 to 12/2010 were evaluated, and corresponding data were analyzed. There were 11 pediatric and 14 adult recipients. Median donor age and body weight were 38 months and 14 kg, respectively. PNF, n = 2 and DGF, n = 1 were observed only among adult recipients. Five-yr graft survival was 100% for children and 86% for adults. There were no significant differences in graft and patient survival, PNF, DGF, acute rejection, or postoperative complications among children/single (n = 10), adults/en bloc (n = 10), and adults/single (n = 4) KT. Major complications were documented in six adult recipients and one pediatric recipient after en bloc KT. Pediatric recipients showed significantly higher GFR during the first post-transplant year. Kidneys from donors ≤5 yr of age have at least as good outcomes as when transplanted as single allografts into children. Although the study-volume is small, it seems that children benefit from a pediatric-oriented allocation policy.


Asunto(s)
Fallo Renal Crónico/cirugía , Trasplante de Riñón/métodos , Donantes de Tejidos , Adulto , Factores de Edad , Niño , Preescolar , Funcionamiento Retardado del Injerto/epidemiología , Funcionamiento Retardado del Injerto/etiología , Femenino , Rechazo de Injerto/epidemiología , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Lactante , Estimación de Kaplan-Meier , Fallo Renal Crónico/mortalidad , Trasplante de Riñón/mortalidad , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento
16.
Digestion ; 86(2): 107-13, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22846254

RESUMEN

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) with its progressive form nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease in western countries which is associated with end-stage liver disease and hepatocellular carcinoma (HCC). This entity is a consistently increasing indication for transplantation. However, data about postsurgery outcome and complications are still limited. PATIENTS AND METHODS: Records of 432 consecutive transplanted patients between October 2007 and January 2011 were investigated retrospectively. Forty transplants were performed due to NASH-induced cirrhosis. Perioperative courses and short- and long-term outcomes were analyzed. RESULTS: The NAFLD population consisted of 16 women and 24 men with a mean age of 55 years. The median MELD score was 27 at the time of liver transplantion. BMI before surgery ranged from 21 to 45 (mean 31). Sixteen of the initial 40 patients are still alive. Patients with sustained obesity and features of the metabolic syndrome had a worse 1-year mortality rate of 42%. CONCLUSIONS: A significant number of liver transplantations in our center was performed due to NASH; transplantation in this cohort was associated with high mortality and postoperative complications, most likely due to associated obesity and diabetes. Weight reduction prior to surgery may lead to a better outcome.


Asunto(s)
Hígado Graso/cirugía , Cirrosis Hepática/cirugía , Trasplante de Hígado/mortalidad , Complicaciones Posoperatorias/epidemiología , Adulto , Anciano , Índice de Masa Corporal , Estudios de Cohortes , Complicaciones de la Diabetes/epidemiología , Hígado Graso/complicaciones , Femenino , Supervivencia de Injerto , Humanos , Cirrosis Hepática/etiología , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/epidemiología , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico , Obesidad/complicaciones , Obesidad/epidemiología , Disfunción Primaria del Injerto/epidemiología , Reoperación , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
17.
Int Urol Nephrol ; 44(5): 1417-23, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22752500

RESUMEN

BACKGROUND: Prolonged cold ischemia time (CIT) has been associated with inferior graft survival in kidney transplantation (KT). The aim of this study was to evaluate the impact of prolonged CIT on short- and long-term outcomes and to determine the possible ways to optimize the use of these organs. METHODS: All kidney transplants from April 2001 to December 2010 with CIT ≥ 20 h were considered. Donor and recipient data were analyzed with uni- and multivariate Cox proportional hazard analyses. Graft and patient survival were calculated using the Kaplan-Meier method. RESULTS: One hundred and eighty-one patients were transplanted with 184 grafts. Median recipient age and waiting time on dialysis were 52.5 and 4.9 years, respectively. After a median follow-up of 4.9 years, 148 of 181 patients are alive, 143 of them with functioning grafts. One-, three, and five-year graft and patient survival rates were 90, 87, and 79 %, and 96, 91, and 85 %, respectively. Donor age (p < 0.0001), retransplantation (p = 0.0025), and induction therapy with interleukin-2 antagonists (p = 0.0487) were predictors of graft survival by univariate analysis. Donor age and retransplantation remained significant by multivariate analysis (p < 0.001 and p = 0.0046, respectively). Donor age (p = 0.0176) and creatinine level at 1-month post-KT (p = 0.0271) were predictors of patient survival by univariate analysis. Only donor age reached multivariate significance (p = 0.0464). The calculated donor age cut off was 60 years. CONCLUSIONS: Satisfactory long-term kidney transplant outcomes in the setting of CIT ≥ 20 h can be achieved with grafts from donors <60 years in first-time recipients. Induction therapy should preferably be with an interleukin-2 antagonist.


Asunto(s)
Isquemia Fría/efectos adversos , Funcionamiento Retardado del Injerto/etiología , Supervivencia de Injerto , Trasplante de Riñón/efectos adversos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Creatinina/sangre , Femenino , Humanos , Interleucina-2/antagonistas & inhibidores , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Reoperación , Estudios Retrospectivos , Factores de Tiempo , Adulto Joven
18.
Hepatogastroenterology ; 58(109): 1110-1, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21937359

RESUMEN

Hemorrhagic pancreatitis, especially in the setting of multiorgan dysfunction and generalized peritonitis, is characterized by a very high mortality rate. We herein describe the unique case of a patient who survived 27 consecutive laparotomies. This favourable outcome highlights the complexity of the underlying pathology as well as the challenges faced by the treating team.


Asunto(s)
Laparotomía , Pancreatitis/cirugía , Peritonitis/terapia , Femenino , Humanos , Persona de Mediana Edad , Reoperación
19.
Hepatogastroenterology ; 58(107-108): 738-9, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21830380

RESUMEN

BACKGROUND/AIMS: The aim of this study was to analyze the risk for surgical complications after kidney transplantation in patients with diabetes mellitus (DM) compared to patients without DM. METHODOLOGY: Between January 2002 and December 2005 270 consecutive kidney transplantations from deceased donors in adult recipients were performed. Data of these patients were analyzed on the presence of DM. Recipients with DM (n=32) were compared with patients without DM (n=238) concerning delayed graft function, wound infections, urinary leakage, postoperative bleeding and urinary infections. RESULTS: No statistically significant differences were found in the occurrence of delayed graft function, postoperative bleeding and urinary tract infections between both groups. Although the percentage of postoperative wound infections and urinary leakages was elevated in the DM group it was not statistical significant. CONCLUSION: In patients with terminal kidney insufficiency the presence of DM type II is a frequent co-morbidity and is per se not a contraindication for kidney transplantation. Because of the elevated cardiovascular risk profile patients with DM have to be evaluated very diligent before being listed for kidney transplantation. Nevertheless beside the additional short term risk caused by kidney transplantation it is the only modifiable risk with possible long term reduction for these patients.


Asunto(s)
Nefropatías Diabéticas/cirugía , Trasplante de Riñón/efectos adversos , Humanos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Infecciones Urinarias/epidemiología , Infecciones Urinarias/etiología
20.
Liver Int ; 31(7): 1021-7, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21733092

RESUMEN

BACKGROUND: The disparity between the demand for solid organs and the current supply is a growing problem for patients with end-stage liver disease. To overcome organ shortage, extended criteria donor organs are also accepted for liver transplantation. AIMS: We here unprecedentedly report the clinical course of patients receiving livers with markedly elevated liver enzymes. METHODS: Between November 2007 and December 2010, 15 donor livers with markedly elevated liver enzymes [median aspartate aminotransferase (AST) 1400 (500-7538) U/l, median alanine aminotransferase (ALT) 1026 (308-9179) U/l] were offered to our transplant centre. Based on elaborate judgment, seven of these donor livers were rejected and eight donor livers were transplanted. RESULTS: All eight transplanted patients showed a liver enzyme peak on the day of surgery (AST 2076 ± 1808 U/l, ALT 1087 ± 833 U/l) and a statistically significant decrease from day 0 to day 7 post-liver transplantation. INR decreased and platelet count increased statistically significantly within 1 week after liver transplantation. The patients were discharged from the hospital 28 ± 11 days after liver transplantation in good clinical condition. CONCLUSIONS: These data demonstrate that using donor livers with markedly elevated liver enzymes may be an acceptable option to expand the donor pool. Universal objective parameters for acceptance should be defined in future studies.


Asunto(s)
Alanina Transaminasa/metabolismo , Aspartato Aminotransferasas/metabolismo , Enfermedad Hepática en Estado Terminal/cirugía , Trasplante de Hígado/métodos , Hígado/enzimología , Donantes de Tejidos/provisión & distribución , Trasplantes/normas , Humanos , Trasplante de Hígado/normas , Resultado del Tratamiento
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