Experimental study on hepatic reinnervation after orthotopic liver transplantation in rats

BACKGROUND/AIMS: The present study examined whether extrinsic hepatic reinnervation occurred after orthotopic liver transplantation (OLT) in rats. METHODS: Inbred male Lewis rats were the recipients and females the donors. Tissue specimens were obtained postoperatively from the stump of a recipient's hepatoduodenal ligament (A), and the hepatic hilus (B) and peripheral parenchyma (C) of liver allografts, up to 6 months post-operation. Specimens were subjected to immunohistochemical examination using growth-associated protein (GAP)-43 as an axonal marker and transmission electron microscopy (TEM) for observing regenerating axons, as well as the polymerase chain reaction assay to detect the rat sex-determining region Y (SRY) protein gene of the regenerating nerves. RESULTS: At site A, GAP-43-positive nerve axons were identified from day 1 to 1 month post-OLT and SRY protein genes were expressed at and after 3 days post-OLT. At site B, GAP-43-positive axons were observed between 3 days and 1 month, and SRY protein genes were detected at 1 month post-OLT and thereafter. TEM confirmed the presence of regenerating axons at and after 3 days post-OLT. CONCLUSIONS: The results demonstrated that regenerating nerve fibers originating from the recipients reinnervated liver allografts. This extrinsic innervation occurred shortly after OLT, and most likely terminated after about 3 months.     

Mechanism of cold ischemia-reperfusion-induced graft injury after orthotopic liver transplantation in rats

BACKGROUND/AIMS: The purpose of this study was to clarify the mechanism of cold ischemia-reperfusion-induced graft injury after liver transplantation, especially with regard to the relationship between hepatocyte, sinusoidal endothelial cell injury, and hepatic hemodynamic alteration. METHODOLOGY: We evaluated changes in hepatocyte and sinusoidal endothelial cell function, and hepatic hemodynamics after reperfusion in an isogeneic rat liver-transplantation model. The livers of male LEW rats were stored in 4 degrees C lactated Ringer's solution for 1 hr, 3 hr (viable graft), and 6 hr (nonviable graft) before implantation. After reperfusion, hepatocyte function was assessed by serum alanine aminotransferase level and bile output; sinusoidal endothelial cell function was evaluated by serum hyaluronic acid level. Furthermore, we measured hepatic venous oxygen saturation, and portal venous blood flow using a transit time blood flow meter. RESULTS: At 2 hr after reperfusion, the hepatocyte function was similar in all groups. However, the sinusoidal endothelial cell function deteriorated severely in the nonviable graft group, and significantly decreased hepatic venous oxygen saturation levels were observed, suggesting poor hepatic circulation. At 4 hr after reperfusion, the hepatocyte injury was markedly increased in the nonviable graft group. Although systemic blood pressure remained stable, significantly decreased portal venous blood flow in the nonviable graft group was found compared with the viable graft groups. Histopathological studies showed that massive ischemic necrosis was seen in zone III (central) of hepatic lobule 8 hr after reperfusion in the nonviable graft group. CONCLUSIONS: These data suggest that the sinusoidal endothelial cell injury was predominant in the early phase of reperfusion, and might cause microcirculatory disturbances, resulting in decreased portal venous blood flow. This phenomenon may subsequently cause ischemic damage to the hepatocyte, with eventual graft failure.     

Recurrence of the Budd-Chiari syndrome after orthotopic liver transplantation.

Obstruction of the hepatic venous outflow with or without involvement of the vena cava results in the Budd-Chiari syndrome (BCS). BCS may be limited to the liver but there is a variety of systemic disorders forming the etiology of BCS in the majority of cases. Surgery has a major impact on treatment of the BCS within a wide range of therapeutic strategies. The ultimate option of surgical management of the BCS is orthotopic liver transplantation (OLTx). The case of a patient with recurrent disease more than 5 years after OLTx for BCS due to paroxysmal nocturnal hemoglobinuria is analyzed with complete documentation. The literature is reviewed and the probable underlying causes for recurrent disease after OLTx for BCS are discussed including therapeutic consequences.     

Arrhythmias after orthotopic heart transplantation

BACKGROUND: Arrhythmias frequently occur after orthotopic heart transplantation (OHT). METHODS AND RESULTS: The most common are ventricular premature complexes, atrial premature complexes, sinus or junctional bradycardia, atrial fibrillation, and atrial flutter, all of which have varying clinical significance depending on associated or causative conditions. Unique etiologic factors such as allograft rejection, transplant coronary artery disease, and altered anatomy and autonomic nervous system changes require that arrhythmias be treated differently after OHT compared with the general population. CONCLUSION: The potentially severe ramifications of allograft rejection and coronary artery disease make treatment of these disorders in the setting of arrhythmias as important as treating the arrhythmias themselves. At the same time, autonomic denervation and altered anatomy after transplantation complicate drug and device therapies.     

Ischemic-type biliary complications after orthotopic liver transplantation.

Nonanastomotic biliary strictures that involve only the biliary tree of the graft occur after orthotopic liver transplantation in patients with hepatic artery thrombosis, chronic ductopenic rejection and ABO blood group incompatibility. This complication may also occur in the absence of these known risk factors. The major focus of our study was to evaluate the risk factors for nonanastomotic biliary stricturing of unknown cause after orthotopic liver transplantation. Results demonstrate that the development of biliary strictures is strongly associated with the duration of cold ischemic storage of allografts in both Euro-Collins solution and University of Wisconsin solution. Results also demonstrate that strictures are not associated with the type of biliary reconstruction, the primary liver disease, cytomegalovirus infection, allograft rejection or the presence of a positive lymphocytotoxic crossmatch. More recently, we have markedly reduced the occurrence of nonanastomotic biliary stricturing by decreasing the ischemia time of our allografts. Thus nonanastomotic biliary strictures appear to be the result of the ischemia/reperfusion-induced tissue injury associated with the harvest and implantation of allografts.     

Preserved incretin effect in type 1 diabetic patients with end-stage nephropathy treated by combined heterotopic pancreas and kidney transplantation

Insulin secretion is stimulated better by oral than by intravenous glucose (incretin effect). The contribution of the autonomic nervous system to the incretin effect after oral glucose in humans is unclear. We therefore examined nine type 1 diabetic (insulin-dependent) patients with end-stage nephropathy, studied after combined heterotopic pancreas and kidney transplantation, and 7 non-diabetic kidney recipients (matched for creatinine clearance and immunosuppressive medication). The release of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) immunoreactivity and B cell secretory responses (IR insulin and C-peptide) to oral (50 g) and isoglycaemic intravenous glucose (identical glycaemic profile) were measured by radioimmunoassay. The difference in B cell responses between the two tests represents the contribution of the enteroinsular axis to the responses after oral glucose (incretin effect). Insulin responses after the oral glucose challenge were similar in the two patient groups despite systemic venous drainage of the pancreas graft in the pancreas-kidney-transplanted group. In both groups GIP and GLP-1 increased after oral but not after intravenous glucose, and B cell secretory responses were significantly smaller (by 55.2 ± 7.7% and 46.5 ± 12.5%, respectively) with isoglycaemic intravenous glucose infusions. The lack of reduction in the incretin effect in pancreas-kidney-transplanted patients, whose functioning pancreas is denervated, indicates a lesser role for the nervous system and a more important contribution of circulating incretin hormones in mediating the enteroinsular axis in man.     

In vivo suppressive effect of nudear factor-κB inhibitor on neutrophilic inflammation of grafts after orthotopic liver transplantation in rats

AIM. To investigate the effect of pyrrolidine dithiocarbamate (PDTC), a novel nuclear factor-κB (NF-κB) inhibitor, on expression of multiple inflammatory mediators and neutrophilic inflammation of cold preserved grafts after rat liver transplantation and its significance.METHODS: Orthotopic liver transplantation (OLT) was performed after 24 h of cold storage using University of Wisconsin solution with varied concentrations of PDTC. We determined the time course of NF-κB activation and expression of multiple inflammatory signals, such as tumor necrosis factor-α (TNF-α), cytokine-inducible neutrophil chemoattractant (CINC), and intercellular adhesion molecule-1(ICAM-1) by ELISA methods. Serum alanine aminotransferase (ALT), intrahepatic myeloperoxidase (MPO)/WBC (a measure of neutrophil accumulation) and Mac-1 expression (a measure of circulating neutrophil activity) were also evaluated.RESULTS: PDTC decreased NF-κB activation induced by prolonged cold preservation in a dose dependent manner (from 20 mmol/L to 60 mmol/L), diminished TNF-α, CINC,ICAM-1 proteins in the grafts, and reduced the expression f increases in plasma TNF-α levels induced by prolonged old preservation. Neutrophilic inflammation of the graft was significantly suppressed after preservation with PDTC (P<0.05). The total neutrophil accumulation in PDTC (40 mmol/L) group (7.04±0.97) was markedly reduced compared to control group (14.07±1.31) (P<0.05). Mac-1 expression was significantly reduced in PDTC (40 retool/L) group (181±11.3%) compared with the control group (281±13.2%) (P<0.05) at 6 h after reperfusion. Furthermore,PDTC inhibited the increased serum ALT levels after liver transplantation.CONCLUSION: PDTC can inhibit B NF-κB activation and expression of the inflammatory mediators, which are associated with improved graft viability via inhibiting intrahepatic neutrophilic inflammation. Our study suggests that a therapeutic strategy directed at inhibition of NF-κB activation in the transplanted liver might be effective in reducing intrahepatic neutrophilic inflammation, and would be beneficial to cold preserved grafts,     

Neurological complications after orthotopic liver transplantation

BACKGROUND: The number of orthotopic liver transplantation performed each year is increasing due to increased safety and logistic facilities. Therefore, the importance of reducing adverse events is progressively growing. AIM: To review present knowledge on the neurological complications of orthotopic liver transplantation. METHODS: The epidemiology, the clinical features and the pathophysiology of the neurological complications of orthotopic liver transplants, resulting from a systematic review of the literature in the last 25 years, are summarized. RESULTS AND CONCLUSIONS: The review highlights that a relevant variety of neurological adverse events can occur in patients undergoing orthotopic liver transplantation. The knowledge of neurological complications of orthotopic liver transplantation is important for transplantation teams to reduce their prevalence and improve their management. In addition, the likelihood of neurological adverse effects provides evidence for the need of a careful cognitive and neurological work up of patients in the orthotopic liver transplantation waiting list, in order to recognize and interpret neurological dysfunction occurring after orthotopic liver transplantation.     

Colorectal cancer after orthotopic liver transplantation

There is an increased incidence of de novo malignancies in post-liver transplant patients, commonly associated with chronic viral infection comprising lymphoproliferative disease and skin cancers, including squamous cell carcinoma and Kaposi's sarcoma. The overall incidence of colorectal cancer however in this population seems to be no different to the age and sex matched general population. In identified high risk patients like those with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), the incidence of colorectal cancer appears to be higher. In IBD, like other pre-malignant conditions, the risk of developing malignancy increases exponentially with time, raising the question of whether the apparent increase in the incidence of colorectal cancer is the result of liver transplantation and immunosuppression or due to the natural history of IBD. For these PSC recipients, pre-transplant screening with colonoscopy and post-transplant surveillance for malignant change in the large bowel is crucial. The behaviour of inflammatory bowel disease post-liver transplant is largely unpredictable despite immunosuppression. Colorectal cancer when it occurs in the post-liver transplant patient should be managed according to current guidelines, stage for stage as for the population in general coupled with reduction in immunosuppression treatment.     

Bone disease after orthotopic liver transplantation

After orthotopic liver transplantation (OLT), not infrequently a deterioration of bone disease leading to compression fractures of vertebrae is seen. In a consecutive series of 36 adult OLT patients, we studied, clinically and radiologically, the incidence and degree of bone disease before and after OLT; we also studied whether clinical, radiological and laboratory findings were related to the event of postoperative vertebral collapse. Before OLT, radiological signs of mostly slight osteoporosis were seen in a minority of patients. After OLT, 38% of patients developed vertebral collapse, mainly in the second trimester. Collapse occurred in both previously normal and abnormal vertebrae. Of the preoperative parameters sex, age, menopause, intake of prednisolone, duration and diagnosis of liver disease, duration and degree of cholestasis, bone radiology and urinary calcium, only a low urinary calcium was related to postoperative collapse. Of the postoperative parameters duration of cholestasis, urinary calcium, duration of hospital stay, prednisolone dose and outcome in terms of life and death, none was related to collapse. We conclude that vertebral collapse after OLT occurs frequently and is not easily predicted. Early prevention of bone disease in patients with chronic liver disease before OLT and a low steroid-containing immunosuppressive regimen after OLT are advocated.     

Long-term follow-up after orthotopic heart transplantation

While infection and acute rejection continue to be the most frequent cause of early postoperative mortality, chronic rejection including both coronary vasculopathy and unspecific myocardial allograft failure and side effects of immunosuppressive therapy determine late survival and quality of life. Some data are presented of a systematic program for long-term follow-up of cardiac transplant recipients with particular emphasis on coronary vasculopathy and modern concepts in rejection detection and control. Infections remain a notable source of morbidity and mortality. The importance of continued efforts to prevent infection even in the Cyclosporin era has to be emphasized. Tricuspid insufficiency is influenced by the mismatch of recipient and donor heart size. Intraoperative adaptation of the recipient pericardium to the size of the donor heart reduces the magnitude. Unspecific graft failure has been observed to occur at an incidence of 8% three years after transplantation. Three types of rejection can be distinguished after heart replacement, the hyperacute rejection as a rare complication precipitated by preformed recipient antibodies to donor antigens, the acute rejection as a major risk factor for survival in the postoperative first year, and, finally, the chronic rejection which is an important factor for long-term survival and quality of life. Considering the detection and classification of the acute rejection, a semiquantification is advantageous because of its therapeutic relevance. The chronic rejection is characterized by vascular abnormalities, interstitial changes, and myocardial alterations. Of these, the vascular component is the most important clinically. The incidence of this coronary vasculopathy, taking all forms visible angiographically, is about 30-40% of surviving patients three years after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fatal hyperammonemia after orthotopic lung transplantation

BACKGROUND: A case of fatal hyperammonemia complicating orthotopic lung transplantation was previously reported. OBJECTIVE: To describe the incidence, clinical features, and treatment of hyperammonemia associated with orthotopic lung transplantation. DESIGN: Retrospective cohort analysis. SETTING: Academic medical center and lung transplantation center in Philadelphia, Pennsylvania. PATIENTS: 145 sequential adult patients who underwent orthotopic lung transplantation. MEASUREMENTS: Plasma ammonium levels. RESULTS: Six of the 145 patients who had had orthotopic lung transplantation developed hyperammonemia, all within the first 26 days after transplantation. The 30-day post-transplantation mortality rate was 67% for patients with hyperammonemia compared with 17% for those without hyperammonemia (P = 0.01). Development of major gastrointestinal complications (P = 0.03), use of total parenteral nutrition (P < 0.001), and lung transplantation for primary pulmonary hypertension (P = 0.045) were associated with hyperammonemia. CONCLUSIONS: Hyperammonemia is a potentially fatal event occurring after orthotopic lung transplantation. It is associated with high nitrogen load, concurrent medical stressors, primary pulmonary hypertension, and hepatic glutamine synthetase deficiency.     

Infectious complications after orthotopic liver transplantation

Advances in surgical technique, critical care, immunosuppression, donor and recipient screening, and prophylactic strategies have contributed to the evolving microbiology and epidemiology of infectious complications after liver transplantation. Although decreased overall, infections continue to be a major contributor to graft loss and patient morbidity. Bacterial and candidal infections are less frequent, but antimicrobial resistance has become more common and can potentially limit successful treatment of health care-acquired and surgical site infections. As the transplant population grows, intensivists and pulmonologists are more likely to evaluate liver transplant recipients with infections. Presentations of opportunistic respiratory infections may be atypical in the setting of immunosuppression. Although novel noninvasive diagnostic tools are available for some pathogens, bronchoscopic evaluation may be increasingly helpful in differentiating between certain respiratory pathogens when empirical therapy is plagued by drug interactions and drug toxicities. Knowledge about common postoperative infections and opportunistic respiratory pathogens such as cytomegalovirus and fungi is essential to improving the global care of the liver transplant recipient.     

Tubular function after orthotopic liver transplantation

Renal function after orthotopic liver transplantation (OTL) is very frequently reduced and its level exerts a significant effect on the morbidity and mortality of these subjects. One of the main factors with a negative impact on renal function after OTL is the nephrotoxic action of cyclosporin A (CsA). Renal function after OTL is usually evaluated on the basis of glomerular filtration (GF). As chronic nephrotoxicity of CsA is manifested in the histological picture by significant tubulointerstitial affection, in 75 subjects after OTL the spontaneous concentrating and acidifying capacity of the kidneys was investigated. The value of urine osmolality (UOSM) assessed after noctunal withdrawal of fluids was in 72.7% lower than in healthy subjects and did not reach 600 mOsm/kg H2O, although the serum creatinine concentration (Scr) was still within the normal range. The pH value of the morning urine did not reach in 38.2% the required value of 6.0 although Scr was within the normal range. Between values of UOSM after nocturnal liquid withdrawal and GF assessed on the basis of inulin clearance (Cin) was a significant direct relationship, however the scatter of values was considerable (r = 0.226, p < 0.05). Between pH values of the morning urine and Cin no correlation was found. The assembled results support the idea that the concentrating activity of the kidneys in subjects after OTL treated with CsA is reduced. This reduced concentrating capacity is already apparent on the basis of UOSM of morning urine after nocturnal fluid withdrawal. Although this defect is also frequent in subjects with a normal Scr value, the authors assume that the use of this simple evaluation of the concentrating capacity (it does not burden the patient nor the attending staff) could be useful in the early diagnosis of tubulointerstitial affection.     

Transesophageal echocardiography after orthotopic heart transplantation

Conclusion TEE, which was for the first time used for evaluation of transplant patients in this study, yielded important information on the morphology and function of the transplanted heart, which cannot be obtained by TTE. The TEE findings indicate the need for antiplatelet therapy in patients with SEC and provide a potential clue to the pathogenesis of the AV valve incompetence.Supported by a Research Grant of the Wilhelm Sander-Foundation (AZ 86.015.2)     

二步法大鼠原位全小肠移植模型的建立与改进

目的:建立一种简单稳定、死亡率低的二步法大鼠原位小肠移植模型.方法:整块获取带肠系膜上动脉的腹主动脉和门静脉的全小肠,血管重建采用供体腹主动脉和受体腹主动脉端侧吻合、供体门静脉和受体左肾静脉端套管吻合.受体第一步手术时,供肠远端端侧吻合于受体的末端回肠,已结扎的供肠近端固定于右侧腹壁(不做腹壁造口).7d后行第2步手术,自Tritze韧带下1cm到回肠吻合口上1cm切除受体小肠,受体空肠残端端侧吻合于供肠近端.结果:共进行二步法大鼠原位小肠移植手术174次,正式实验44次,手术成功率90.9%.受体第1次手术时间约50±15 min,其中动脉吻合时间约为20±5 min,静脉吻合时间2±1 min,受体第2次手术时间约35±15 min.4只大鼠死于第一次手术后5 d内,2只死于肠瘘,1只死于麻醉意外,1只死于肠梗阻.第2次术后没有大鼠死亡,40只大鼠均长期存活(超过3 mo).结论:二步法大鼠原位小肠移植方法安全可靠,并发症少,生存率高.