HIV and solid organ transplantation: the Swiss experience.
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Cohort Studies↗
Biomedical subjects
Daniel Candinas
Publications and source records attributed to Daniel Candinas.
Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication.
Hypermutations in hepatitis B virus (HBV) DNA by APOBEC3 cytidine deaminases have been detected in vitro and in vivo, and APOBEC3G (A3G) and APOBEC3F (A3F) have been shown to inhibit the replication of HBV in vitro, but the presumably low or even absent hepatic expression of these enzymes has raised the question as to their physiological impact on HBV replication. We show that normal human liver expresses the mRNAs of APOBEC3B (A3B), APOBEC3C (A3C), A3F, and A3G. In primary human hepatocytes, interferon alpha (IFN-alpha) stimulated the expression of these cytidine deaminases up to 14-fold, and the mRNAs of A3G, A3F, and A3B reached expression levels of 10%, 3%, and 3%, respectively, relative to GAPDH mRNA abundance. On transfection, the full-length protein A3B(L) inhibited HBV replication in vitro as efficiently as A3G or A3F, whereas the truncated splice variant A3B(S) and A3C had no effect. A3B(L) and A3B(S) were detected predominantly in the nucleus of uninfected cells; however, in HBV-expressing cells both proteins were found also in the cytoplasm and were associated with HBV viral particles, similarly to A3G and A3F. Moreover, A3G, A3F, and A3B(L), but not A3B(S), induced extensive G-to-A hypermutations in a fraction of the replicated HBV genomes. In conclusion, the editing enzymes A3B(L), A3F, and most markedly A3G, which are expressed in liver and up-regulated by IFN-alpha in hepatocytes, are candidates to contribute to the noncytolytic clearance of HBV.
Base Sequence↗
Regenerative capacity of individual liver lobes in the microsurgical mouse model.
In the development of microsurgical mouse models of hepatic regeneration and repair, lobe-specific regenerative responses were observed. We therefore determined the hepatic regenerative capacity of individual mouse liver lobes. In mice, 26, 60, 75, and 83% of total liver mass was resected. Bromo-deoxyuridine (BrdU) was injected prior to liver harvest and the BrdU labeling index determined in all remaining individual liver lobes. BrdU-positive nuclei were seen in all liver lobes after the 26 and 60% resection, but significantly fewer were detected in the caudate lobe. In the 75% group, equally distributed positive nuclei were found. However, BrdU labeling was scant in the 83% group. In microsurgical mouse liver-regeneration models, the average hepatic response depends on amount of liver tissue resected and on the remaining liver lobe. BrdU incorporation can vary significantly among individual lobes. The lobe-specific differences observed may prove valuable in further investigations of hepatic regeneration and repair.
Animals↗
Early renal failure after domino hepatic transplantation using the liver from a compound heterozygous patient with primary hyperoxaluria.
BACKGROUND: To cover the shortage of cadaveric organs, new approaches to expand the donor pool are needed. Here we report on a case of domino liver transplantation (DLT) using an organ harvested from a compound heterozygous patient with primary hyperoxaluria (PHO), who underwent combined liver and kidney transplantation. The DLT recipient developed early renal failure with oxaluria. The time to the progression to oxalosis with renal failure in such situations is unknown, but, based on animal data, we hypothesize that calcineurin inhibitors may play a detrimental role. METHODS: A cadaveric liver and kidney transplantation was performed in a 52-year-old male with PHO. His liver was used for a 64-year-old patient with a non-resectable, but limited cholangiocarcinoma. RESULTS: While the course of the PHO donor was uneventful, in the DLT recipient early post-operative, dialysis-dependent renal failure with hyperoxaluria developed. Histology of a kidney biopsy revealed massive calcium oxalate crystal deposition as the leading aetiological cause. CONCLUSIONS: DLT using PHO organs for marginal recipients represents a possible therapeutic approach regarding graft function of the liver. However, it may negatively alter the renal outcome of the recipient in an unpredictable manner, especially with concomitant use of cyclosporin. Therefore, we suggest that, although DLT should be promoted, PHO organs are better excluded from such procedures.
Bile Duct Neoplasms↗
Severe acute pancreatitis: case-oriented discussion of interdisciplinary management.
The clinical course of an episode of acute pancreatitis varies from a mild, transitory illness to a severe often necrotizing form with distant organ failure and a mortality rate of 20-40%. Patients with severe pancreatitis, representing about 15-20% of all patients with acute pancreatitis, need to be identified as early as possible after onset of symptoms allowing starting intensive care treatment early in the disease process. An episode of severe acute pancreatitis progresses in two phases. The first 10-14 days are characterized by a systemic inflammatory response syndrome maintained by the release of various inflammatory mediators. The second phase, beginning about 10-14 days after the onset of the disease is dominated by sepsis-related morbidity due to infected peripancreatic and pancreatic necrosis. This state is associated with septic multiple organ systemic failure. The importance of infection on the outcome of necrotizing pancreatitis has been clearly delineated and the pre-emptive use of broad-spectrum antibiotics that achieve effective tissue concentrations is considered standard management of patients with severe necrotizing pancreatitis, especially if associated with organ failure or extended necrosis. Patients with infected necrosis should undergo a surgical intervention. The standard open technique consisting of an organ preserving necrosectomy followed by a postoperative concept of lavage and/or drainage to evacuate necrotic debris occurring during the further course has recently been challenged by various minimally invasive approaches.
Acute Disease↗
Interleukin-3 induces hepatocyte-specific metabolic activity in bone marrow-derived liver stem cells.
Bone marrow-derived adult liver stem cells (BALSC) are a promising target for the development of future cell-based therapies for a variety of liver disorders. However, the ability of stem cells to fully function, as hepatocytes, is limited and differentiation is time dependent. Therefore, it will be conducive to find a growth factor that is able to enhance liver-specific metabolic activity in freshly isolated liver stem cells. Recently, a subpopulation of BALSC was isolated and characterized (beta2-microglobulin-negative/ Thy-1-positive cells). We hypothesized that using interleukin-3 (IL-3), a hematopoietic differentiation growth factor, we may be able to enhance liver-specific metabolic activity in freshly isolated BALSC. Rat BALSC from normal and injured livers (bile duct ligated) were isolated and stimulated with IL-3 in culture. Cells were co-cultured with or without hepatocytes, separated by a semipermeable membrane. We measured the effect of IL-3 on BALSC to metabolize ammonia into urea (a liver-specific metabolic activity). IL-3 increased the ability of BALSC, purified from normal animals, to metabolize ammonia into urea by several folds. Interestingly, no such effect was found in cell cultures from bile duct-ligated animals. Additionally, co-cultures of BALSC with hepatocytes induced higher rate of ammonia metabolism, which was further enhanced by IL-3. Our study indicates that IL-3 may be used as an agent to enhance differentiation of BALSC, both qualitatively and quantitatively. It is conceivable that stem cells may undergo IL-3 priming before their clinical application in cell transplantation or bioartificial liver systems.
Ammonia↗
Functional comparison of bone marrow-derived liver stem cells: selection strategy for cell-based therapy.
Several distinct subpopulations of bone marrow-derived liver progenitor cells were recently described. However, there is inadequate information comparing these subpopulations from a liver-function point of view. This study was undertaken to compare two subpopulations of liver progenitors: beta(2)-microglobulin (beta(2)m)-negative/Thy-1-positive cells, and liver progenitors obtained from the non-adherent cell fraction after a panning procedure. The cells were cultured under several conditions including high- and low-dose hepatocyte growth factor, various cellular densities, and different media. Growth characteristics, liver-specific metabolic capacity, and liver regeneration-associated gene expression were studied. Both isolation procedures yielded cells that produced albumin and metabolized ammonia into urea. The study demonstrated that the beta(2)m-negative/Thy-1-positive cell fraction metabolized ammonia into urea more efficiently and produced a superior amount of albumin compared with the panned cell fraction. The beta(2)m-negative/Thy-1-positive cell fraction could be optimal for the development of novel cell-based treatment strategies for congenital or acquired liver diseases.
Animals↗
Molecular absorbent recirculating system for the treatment of acute liver failure in surgical patients.
The Molecular Adsorbent Recirculating System (MARS) represents an attractive artificial liver support system for the treatment of liver insufficiency. However, neither indications for MARS treatment (i.e., after extended liver resection) nor criteria for discontinuation of therapy have been evaluated. Therefore, we analyzed the clinical data of all our surgical patients who received MARS treatment for acute liver failure (n = 7). The aim of the study was to identify prognostic indicators for survival. Four of 174 patients resected for hepatic malignancy at our institution received a total of 13 MARS treatments. Two additional patients were successfully bridged to orthotopic liver transplantation with seven MARS treatments and one patient was MARS supported after liver transplantation of a steatotic graft with three MARS treatments. Five of the seven patients survived and were dismissed an average of 31 days, ranging from 17 to 47 days, after the final MARS treatment. No technical complications or adverse effects were observed during the MARS treatments. Important prognostic factors for hepatic recovery and survival were indocyanin green plasma disappearance rates greater than 5%/min and an increase in clotting factor V levels after each MARS treatment. We conclude that MARS therapy can be an effective treatment of postoperative liver insufficiency in the surgical hepatobiliary unit.
Adult↗
Use of a mechanical thrombectomy device to recanalize a subacutely occluded aortohepatic bypass after orthotopic liver transplantation.
PURPOSE: To report the use of a rotational thrombectomy device for recanalization of a thrombosed hepatic artery bypass graft in an orthotopic liver transplant (OLT). CASE REPORT: Six months after a second OLT in a 52-year-old man, an iliac conduit used for an aortohepatic bypass became occluded, interrupting arterial supply to the liver transplant. The 8-F Straub Rotarex system was used to successfully remove clot from the bypass graft, avoiding embolization to the hepatic arteries. The recanalized conduit has remained patent for 1 year with the patient on an anticoagulation regimen. CONCLUSIONS: The Rotarex thrombectomy system may be considered an alternative to other percutaneous interventions for the treatment of occluded bypass conduits supplying a liver transplant.
Anastomosis, Surgical↗
The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants.
Point mutations constitute a major mode of oncogenic activation of the Met receptor tyrosine kinase. Met is aberrantly activated in many types of human malignancies and its deregulated activity is correlated with aggressive tumor traits such as abnormal proliferation and survival, leading to tumor growth, local invasion and metastasis. Here we report that the Met kinase inhibitor SU11274 differentially affects the kinase activity and subsequent signaling of various mutant forms of Met. Two Met variants tested, M1268T and H1112Y, were potently inhibited by 2 microM SU11274, while two other variants, L1213V and Y1248H, remained resistant under similar experimental conditions. Inhibition of the kinase altered cell proliferation, morphology and motility, while cells containing resistant mutants appeared unaffected by the compound. The basis for the sensitivity or resistance to SU11274 is discussed in terms of the position of the mutations predicted from a homology model.
Animals↗
Magnetic resonance imaging provides accurate and precise volume determination of the regenerating mouse liver.
Direct and repetitive noninvasive determination of the time course and the strain-specific hepatic regenerative capacity after partial hepatectomy can extend our knowledge about the basic mechanisms of liver regeneration and repair. The aim of this study was to develop a magnetic resonance (MR)-based volumetric procedure to measure the hepatic volume in the regenerating mouse liver. In Balb-C mice (n = 14), varying amounts of liver tissue were resected and MR imaging was performed 24 hours later in a 1.5 Tesla Magnet Unit. Three dimensional (3D) T1- (volumetric interpolated breath-hold examination [VIBE] sequence) and T2-weighted images were acquired with continuous 1-mm thin slices. Animals with and without intravenous administration of paramagnetic contrast agents were compared. Immediately after MR examination, mice were euthanized and livers were weighted. The liver volume was determined on MR images using Cavalieri's method and linear regression analysis was performed from the data obtained. Correlation coefficients between the liver volume measured by MR and the liver weight were 0.98 (T1) and 0.94 (T2) in the group without paramagnetic contrast injection and 0.70 (T1) and 0.96 (T2) after paramagnetic contrast application. We conclude that MR-based liver volumetry allows precise liver volume measurement during hepatic regeneration after partial hepatectomy in mice and can be a valuable tool with regard to experimental hepatology.
Animals↗
Effect of vascular endothelial growth factor on functional recovery after hepatectomy in lean and obese mice.
BACKGROUND/AIMS: Liver regeneration is dependent upon coordinated proliferation of hepatocytes and endothelial cells. Vascular endothelial growth factor (VEGF) promotes angiogenesis. Hepatic steatosis delays regeneration and increases liver resection morbidity. We hypothesized that VEGF overexpression stimulates hepatic regeneration. METHODS: Recombinant adenovirus expressing human VEGF165 or adenovirus control-vector (LacZ) were administered before 2/3 hepatectomy in lean and ob/ob mice. Galactose elimination capacity, a quantitative liver function test, was repeatedly measured before and after hepatectomy. Expression of VEGF receptors (flt1, flk1), endoglin and hypoxia inducible factor-1alpha (HIF-1alpha) was assessed by quantitative RT-PCR and for endoglin also by immunohistochemistry. RESULTS: After 2/3 hepatectomy, VEGF gene transfer increased galactose elimination capacity in lean and ob/ob mice. HIF-1alpha, endoglin and VEGF receptor mRNA increased during regeneration in lean but not in obese mice. Staining of endothelial cells by endoglin immunohistochemistry returned to baseline reactivity in lean mice by day 6 and remained decreased in ob/ob mice. VEGF treatment decreased HIF-1alpha and increased flk1 response in lean mice. CONCLUSIONS: Hepatic resection elicits an angiogenic response in the remnant liver, which is impaired in case of steatosis. Adenovirus-mediated transfer of VEGF hastens functional hepatic recovery in lean, and more importantly also, in obese mice after partial hepatectomy.
Adenoviridae↗
Colorectal cancer in patients with inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis.
BACKGROUND: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) may have an increased risk of developing colorectal cancer (CRC) after liver transplantation (LT). We evaluated our patients with PSC after LT to identify risk factors for CRC and its impact on survival. PATIENTS AND METHODS: A total of 152 patients (108 men, 100 with IBD) with PSC who underwent 173 LTs between 1986 and May 2000 were analyzed in three groups: (1) PSC without IBD (n=52); (2) PSC with colectomy (pre-LT and at LT) (n=17, colectomy pre-LT in 13 and simultaneous colectomy at LT in four); and (3) PSC with IBD and an intact colon (n=83). The following factors were studied: age, gender, liver, and renal biochemistry, international normalized ratio, Child-Pugh stage, operative time, blood use, hospital stay, immunosuppression, risk of CRC, retransplantation rate, and mortality. RESULTS: The incidence of CRC after LT was 5.3% (8/152) compared with 0.6% (7/1,184) in non-PSC cases (P<0.001). All CRCs in the PSC group were in patients with IBD and an intact colon. The cumulative risk of developing CRC in the 83 patients with an intact colon and IBD was 14% and 17% after 5 and 10 years, respectively (PSC non-IBD group 0% risk after 10 years, P<0.06). The multivariate analysis showed three significant variables related to the risk of developing CRC: colonic dysplasia after LT (P<0.0003), duration of colitis more than 10 years (P<0.002), and pancolitis (P<0.004). The cause of death in patients with CRC was cancer related in 75% of cases with a reduced 5-year survival of 55% versus 75% without CRC (not significant). CONCLUSION: Patients with PSC undergoing LT with a long history of ulcerative colitis and pancolitis have an increased risk of developing CRC with reduced survival. We advocate long-term aggressive colonic surveillance and colectomy in selected high-risk patients with longstanding severe colitis.
Adolescent↗
Sinomenine blocks tissue remodeling in a rat model of chronic cardiac allograft rejection.
BACKGROUND: Chronic rejection (CR) with graft vasculopathy is recognized as a major cause of graft loss over time. Sinomenine (SN) has anti-inflammatory, antirheumatic, and immunomodulatory effects. Previously, we demonstrated antimacrophage and anti-T cell effects of SN in acute rejection. In the current study, we investigated the effect of SN in a rat cardiac allograft model of CR. MATERIALS AND METHODS: After a brief course of cyclosporine A (CsA), Lewis recipients of F344 hearts were treated with SN alone, CsA alone, or a combination of both drugs. Grafts were analyzed morphometrically and by immunohistochemistry. Expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and endothelin 1 was assessed by reverse transcription-polymerase chain reaction. Antidonor IgM formation was investigated by FACS. RESULTS: Cardiac grafts from SN-treated rats showed less pronounced vasculopathy in comparison with untreated rats or CsA-treated recipients. After treatment with a combination of both drugs, rats had significantly less graft vasculopathy than rats receiving either drug alone. Treatment with CsA alone led to a decrease in bFGF expression, whereas SN alone did not affect gene expression. SN in combination with CsA, however, markedly reduced expression of bFGF, vascular endothelial growth factor, and endothelin 1. SN alone did not inhibit antidonor antibody formation. CONCLUSION: These studies demonstrate for the first time the therapeutic value of SN in a model of chronic cardiac allograft rejection. SN in combination with low-dose T cell-targeted immunosuppression is effective in controlling tissue remodeling in the context of CR and is associated with inhibition of intragraft expression of mediators involved in angiogenesis, vascular tone, and tissue remodeling.
Adjuvants, Immunologic↗
Hepatic-artery aneurysm in adult liver transplantation.
Hepatic artery aneurysm (HAA) is a rare vascular complication, but has a high mortality rate in liver transplant recipients. This study reports the precipitating factors, clinical manifestation, pre-operative diagnosis, related micro-organism, management, and outcome, in a series of HAAs that developed after adult orthotopic liver transplantation (OLT). Data on the primary disease as well as on the above were obtained from a prospective database, and all case records were reviewed. There were eight (0.5%) HAAs in 1,575 adult cadaveric OLTs between 1982 and March 2001. All were pseudo-aneurysms around the native hepatic-artery (HA) anastomosis, and all occurred in whole-organ OLTs. There were three types of clinical presentations: sudden hypotension (n=4), gastrointestinal (GI) bleeding (n=2), and abnormal liver-function tests (LFTs) (n=2). The majority (n=7) presented within the first 2 months (median: 27.5 days, range: 12-760 days) following OLT. A pre-operative diagnosis of HAA was not determined in five cases. The sensitivity of abdominal ultrasound scan (USS), computed tomography (CT) scan and angiography for detection of HAAs was 3 of 5, 1 of 2 and 3 of 4, respectively. Micro-organisms could be identified in six patients (bacteria n=4 and fungi n=3). All patients underwent urgent operations (excision of HAA in six and ligation in two cases). Immediate reconstruction of the HA was carried out, two different methods being used: repair of native arteries (n=2) and arterial conduit (interposition n=3 and aortic conduit n=2). Two patients died peri-operatively, two died within 2 months, and the remaining four patients are alive at between 8.6 and 12.8 years after repair. HAA following OLT is unpredictable in its presentation, and the sensitivity of clinical and radiological detection is low. A high index of suspicion is required, and urgent surgery with immediate re-vascularisation and use of appropriate antibiotic/anti-fungal agents is recommended.
Adult↗
Worth continuing doing ex situ liver graft splitting? A single-center analysis.
Grafts for split liver transplantation can be prepared in situ during the retrieval operation, or ex situ on the back table. The in situ technique has theoretical advantages because it minimizes the cold ischemic time and allows excellent hemostasis at the cut surface. However, in situ liver division prolongs the retrieval procedure, may precipitate hemodynamic instability in the donor, and may cause logistical difficulties for some centers. This report is a single-center analysis comparing results of ex situ liver division (group I: 1992-97; and group II: 1998-2001) before and after a new protocol for liver graft division was introduced in our center. Eighty-nine split liver transplants (SLT) were reviewed retrospectively. Vascular complications were less common in group II (3.3% vs. 20%; p = 0.04), and 1-year graft survival increased from 59% to 78% (p = 0.03). Since 1998, 1-year graft survival of SLT has been similar to that of conventional liver graft transplantation in our center (78% and 74%, respectively). In conclusion, good results can be achieved from splitting livers ex situ and this procedure should be considered when the in situ technique is not feasible.
Adolescent↗
Ex situ preparation of left split-liver grafts with left vascular pedicle only: is it safe? A comparative single-center study.
The procurement of left-lateral-segment grafts from living donors for transplantation in children is performed by retaining only the left branches of the artery and veins. New techniques and the implementation of microsurgery in the transplant operation made this procedure a successful approach. However, controversy persists about using such an approach for division of liver grafts from cadaveric donors, and many teams prefer retaining the main arterial trunk with the left split graft, with or without the main portal vein trunk. Since 1998, in our center, when a donor-liver graft is divided we prefer retaining the main vessels with the right split graft if graft vascular anatomy is favorable. After 1998, 40 liver grafts from cadaveric donors were divided, and all divisions were performed ex situ. This experience was retrospectively reviewed to compare the outcome of left split grafts prepared for implantation with the left vasculature only (group A), or with the main arterial supply (group B). A single vascular complication occurred (one hepatic artery thrombosis in group B). Three patients died (one in group A and two in group B) and three other grafts were lost (one in group A and two in group B). One-year and 3-year graft survival rates were 94% and 86% in group A, and 83% and 83% in group B, respectively (not significantly [NS] different). We conclude that left split grafts can be safely transplanted with the left vascular supply only, provided that division is guided by careful anatomical evaluation and that vascular reconstructions are adequate.
Adolescent↗
Apoptosis in hypoxic human pancreatic islets correlates with HIF-1alpha expression.
To become insulin independent, patients with type 1 diabetes mellitus require transplantation of at least two donor pancreata because of massive beta-cell loss in the early post-transplantation period. Many studies describing the introduction of new immunosuppressive protocols have shown that this loss is due to not only immunological events but also nonimmunological factors. To test to what extent hypoxia may contribute to early graft loss, we analyzed the occurrence of apoptotic events and the expression of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor consisting of an oxygen-dependent alpha subunit and a constitutive beta subunit. Histological analysis of human and rat islets revealed nuclear pyknosis as early as 6 h after hypoxic exposure (1% O2). Moreover, immunoreactivity to activated caspase-3 was observed in the core region of isolated human islets. Of note, both of these markers of apoptosis topographically overlap with HIF-1alpha immunoreactivity. HIF-1alpha mRNA was detected in islets from human and rat as well as in several murine beta-cell lines. When exposed to hypoxia, mouse insulinoma cells (MIN6) had an increased HIF-1alpha protein level, whereas its mRNA level did not alter. In conclusion, our data provide convincing evidence that reduced oxygenation is an important cause of beta-cell loss and suggest that HIF-1alpha protein level is an indicator for hypoxic regions undergoing apoptotic cell death. These observations suggest that gene expression under the control of HIF-1 represents a potential therapeutic tool for improving engraftment of transplanted islets.
Active Transport, Cell Nucleus↗