Liver function abnormality following treatment with antithymocyte globulin for aplastic anaemia

We describe a neonate with hypotonia, weakness, early death owing to respiratory failure, and a severe form of arthrogryposis multiplex congenita. Postmortem studies revealed numerous ragged-red fibers and central nervous system abnormalities consistent with a mitochondrial disease. No NADH:ubiquinone-1 oxidoreductase (complex I) activity could be detected in skeletal muscle. These findings suggest that mitochondrial cytopathies can be associated with arthrogryposis multiplex congenita and should therefore be sought in neonates presenting with severe arthrogryposis.     

Biliary stenosis in patients treated with liver transplantation. Diagnostic approach

Between April 1986 and August 1994, 393 orthotopic liver transplantation (OLT) have been performed at "12 de Octubre" Hospital. Among these ones we consider 274 OLT made in 223 adults and in 47 children (4 intraoperative deaths). The reconstruction of the biliary tract was performed with a choledocho-choledochostomy with T tube (CD-CD T) in 131 patients, a choledocho-choledochostomy without T tube or stent (CD-CD) in 75, a Roux-en-y-hepatico-jejunostomy (H-J) in 248, a hepatico-jejunostomy with stent (H-J St) in 13 and a choledocho-cholecisto-jejunostomy (CD-CC-J) in 3 patients. Thirthy six (13.3%) patients developed biliary complications (30 adults and 6 childrens). Fourteen (18.6%) occurred in CD-CD reconstruction and 13 (11.4%) in CD-CD T. The most common complications were leakage and stricture. Thirteen ERCP were performed in 12 patients (1 failed), all adults (CD-CD T: 3; CD-CD: 10). The main indication for ERCP was cholestasis and inability of non invasive methods ultrasound, scintigraphy and computerized tomography in determining the underlying etiology. ERCP was successful in all 12 patients: detecting strictures in 8, strictures + lithiasis in 1, stricture+lekage in 1 and leakage in 2. No complications were encountered after ERCP in our patients. ERCP is the method of choice in diagnosis of biliary complications in CD-CD biliary reconstruction.     

Steroid-free immunosuppression after kidney transplantation with antithymocyte globulin induction and cyclosporine and mycophenolate mofetil maintenance therapy

BACKGROUND: Our goal in clinical renal transplantation is to find immunosuppressive procedures that not only promote long-term patient and graft survival but also improve the overall well-being of the patients. METHODS: In a retrospective consecutive clinical study with historical controls, 68 patients were discharged from our center with functioning grafts between September 1995 and December 1997. Patients received steroid-free immunosuppression using an initial 10-day antithymocyte globulin induction and maintenance therapy with cyclosporine and mycophenolate mofetil (MMF). No steroids were given. RESULTS: After an observation for up to 2.5 years (median 488 days, range 127 to 945 days), 66 patients (one died from sepsis after 6 months, and one died of peritonitis after returning to dialysis) were alive and well. Sixty-four grafts were functioning well, hemolytic uremic syndrome recurred in one graft, one graft had to be removed for noncompliance, and two patients returned to dialysis after chronic rejection-one after 8 months (the patient who died in peritoneal dialysis) and one (a third graft in an antibody-positive patient) 16 months after transplantation. We observed only 10 acute rejections (15%), a rate significantly lower (P=0.0006) than the 71 acute rejections observed in 190 previous consecutive transplants (37.4%) treated without MMF but otherwise after exactly the same protocol. In further comparison, the MMF-treated group also showed an equivalent (P=NS) rate of cytomegalovirus infections and a lower rate (P<0.00005) of Epstein-Barr virus infections. Graft function was excellent (median serum creatinine below 200 micromol/L at 1 year), and no malignancies were observed in the MMF-treated patients. Side effects were mainly leukopenia and two gastrointestinal disturbances. CONCLUSIONS: Our first-line, steroid-free immunosuppressive protocol allows initial graft function, provides a safe level of long-term graft survival and function with a very low rejection rate, gives an acceptable rate of side effects, and possesses the potential for lowering the incidence of chronic rejection over the long-term. Compared with protocols that discontinue steroids after the initial posttransplant period, a steroid-free protocol avoids the increased risk of infection and body disfigurement in the early posttransplant period. It also avoids the long-term risks of steroid use and the increased risks of rejection when the steroids are withdrawn.     

Should recurrent Cytomegalovirus infections in patients with liver transplantation be treated?

Cytomegalovirus (CMV) is the single most important viral pathogen in organ transplantation. Treatment strategy for CMV infection and disease is not well established in transplantation. We report a case of primary CMV infection and two relapses in a woman with a liver transplant in whom spontaneous clearing of the second CMV relapse was seen. A 23 year-old CMV-seronegative woman received a liver transplant with a CMV-negative organ. Six weeks after transplantation she had her primary CMV infection proved by seroconversion and virus isolation. She had no clinical symptoms. Treatment with ganciclovir for five weeks resulted in declining CMV-antigen positive cells from 300/200.000 PMNs to CMV-antigen negativity. Only a slight antibody response was seen. At week 13 the first relapse occurred evidenced by antigenaemia. Ganciclovir was reinstituted for six weeks resulting in reduced antigenaemia. At week 22 liver biopsy was performed due to slightly elevated ALAT. The biopsy showed evidence of focal CMV hepatitis and blood analysis showed 120 CMV-antigen positive cells/200.000 PMNs. In spite of this, ganciclovir was not reinstituted, but the immunosuppressive treatment was reduced to a minimum to stimulate the patient's immune response to CMV. During the following months the patient gradually developed IgG antibody, cleared the antigen and levels of liver enzymes returned to normal. We suggest that ganciclovir treatment, may be omitted in cases of relapse with minimal clinical symptoms, slight antigenaemia and a beginning antibody response and that, the immunosuppressive treatment should be reduced instead. Such an approach requires careful clinical monitoring of the patient.     

Heart transplantation in patients with treated breast carcinoma

Since 1987, five women with end-stage cardiomyopathy and a history of treated breast carcinoma have undergone transplantation at our institution. All patients underwent extensive multidisciplinary pretransplantation evaluation to rule out metastatic disease. Disease-free interval before heart transplantation ranged from 5 to 11 years (mean, 7.6 years). All patients received immunosuppression in accordance with a standard protocol of rabbit antithymocyte globulin, cyclosporine, prednisone, and azathioprine. Mean postoperative follow-up is 49 months. All patients are alive and have no symptoms 18 to 73 months after transplantation. In carefully selected patients with a history of breast carcinoma, heart transplantation can be performed with good functional results and satisfactory late survival.     

Liver transplantation in Europe for patients with acute liver failure

Approximately 11% of all liver transplants performed in Europe are for acute liver failure, with one-year patient survival rates ranging between 50% and 75%. This review summarizes the selection, perioperative management, and outcome of patients transplanted for acute liver failure, with particular reference to the experience at the H?pital Paul Brousse in Paris and at King's College Hospital, London. In both centers, the decision to proceed to liver transplantation is based on criteria that predict a survival of less than 20% with medical management alone. Infectious complications and cerebral edema remain the most common causes of death, and highlight the importance of intensive monitoring and early treatment of perioperative complications. In selected patients, auxiliary partial orthotopic liver transplantation may be a therapeutic option, with the potential for native liver generation and eventual immunosuppression withdrawal in approximately two-thirds of patients.     

Selection of patients for liver transplantation

Liver transplantation is now available world-wide. It plays an important role in the treatment of irreversible acute and chronic liver disease (CLD). Selection of patients for liver transplantation is subject to many factors including economic, cultural, availability of donor organs and degree of illness. This article looks at seven general considerations for recipients of liver transplantation. As well, disease-specific criteria are investigated and include such areas as cirrhosis due to chronic hepatitis B virus (HBV), hepatitis C virus (HCV) positive cirrhosis, fulminant hepatic failure (FHF), malignancy, alcoholic liver disease (ALD), metabolic conditions and Budd-Chiari syndrome. If hepatic transplantation survival rates were to approach 95%, the relative risk ratio between transplantation and conservative therapy would increase. At present an 80% 1-5 year survival rate following transplantation should be expected.     

Primary immunosuppression with mycophenolate mofetil and antithymocyte globulin for kidney transplant recipients of a suboptimal graft

BACKGROUND: In renal transplantation the beneficial immunosuppressive effects of cyclosporin (CsA) may be curtailed by its nephrotoxicity, specially in patients receiving a cadaveric allograft from suboptimal donors or at risk of delayed graft function. Mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) have each demonstrated to be potent immunosuppressants in renal transplantation. In a prospective analysis we have studied the results at 6 months of the combination of MMF, ATG and low-dose steroids in patients with low immunological risk receiving a first cadaveric renal allograft from a suboptimal donor or at risk of delayed graft function. METHODS: Patients with preformed reactive antibodies < 500% receiving a first graft from a suboptimal donor (age > or = 40 years, non-heart-beating, acute renal failure, arterial hypertension) or at risk of delayed graft function (cold ischaemia time > or = 24 h) were eligible for this open single-arm pilot trial. From September 1996 to March 1997 we recruited 17 patients. They were treated with MMF 2 g p.o. preoperatively, and after transplantation at 3 g/day; rabbit ATG i.v. at 2 mg/kg preoperatively, and 1.5 mg/kg/day the first day after transplantation, followed by four doses of 1 mg/kg on alternate days; prednisone was given at 0.25 mg/kg/day and reduced progressively to 0.1 mg/kg/day at 3 months. Primary outcomes were incidence of biopsy-proven acute rejection, delayed graft function, opportunistic infections, graft and patient survival, and the need for introduction of CsA treatment. RESULTS: delayed graft function occurred in two cases (12%). Four of 17 patients (24%) had a biopsy-proven acute rejection (2 grade I and 2 grade II) within the first 3 months after transplantation. CsA was added in two cases with grade II biopsy-proven acute rejection, and in one with grade I biopsy-proven acute rejection. In one patient MMF was replaced by CsA because of gastrointestinal intolerance. Mean serum creatinine 6 months after transplantation was 159+/-59 micromol/1. Cytomegalovirus tissue invasive disease occurred in one patient (6%). At 6 months follow-up all patients are alive with functioning allografts. CONCLUSIONS: These preliminary results suggest that in low-immunological-risk patients who receive a suboptimal renal allograft or at risk of delayed graft function, the combination of MMF, ATG, and steroids is an efficient immunosuppressive regime that may avoid the use of CsA in 70% of the recipients.     

Anaesthesia for liver transplantation in cystic fibrosis patients

INTRODUCTION: Cystic fibrosis (CF) is a disease caused by an inherited genetic defect. While pulmonary and pancreatic abnormalities predominate the clinical spectrum, other organ involvement is common, including liver. The severity of liver disease does not appear to be related to the severity of exocrine pancreatic or lung function. We discuss anaesthesia in four CF patients undergoing liver transplantation. METHODS: We studied haemodynamic and oxygenation modifications during anaesthesia in four patients affected by CF with end-stage liver disease and mild to moderate pulmonary abnormalities. The patients received pancreatic enzyme prior to transplantation and two had insulin-dependent diabetes mellitus. All patients were treated with broad-spectrum antibiotic therapy. After a waiting time ranging one week to three months, all patients were successfully transplanted. General anaesthesia was induced with fentanyl, thiopental and pancuronium, and maintained with isoflurane supplemented by fentanyl in O2:air. Haemodynamic and oxygenation evaluations were made during the main phases of the transplant. After the intubation and at the end of the procedure all patients received a broncho-alveolar toilet through fiberoptic bronchoscopy. RESULTS: During anaesthesia for liver transplantation, PaO2 increased proportionally to the decreasing of Qs/Qt. In postoperative follow-up, Fev1 and FVC improved from preoperative time in all patients. In conclusion, even if cystic fibrosis is a multisystem disease, liver transplantation can be offered to CF patients with endstage liver disease and mild to moderate pulmonary function abnormalities. The four patients are still alive, enjoying good health. The improved respiratory function and quality of life of these children is remarkable.     

Outcome of orthotopic liver transplantation in patients with haemophilia

As part of environmental toxicology, it is important to assess both the carcinogenic potential of xenobiotics and their mode of action on target cells. Since dysregulation of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, is considered as an early and essential component in the process of multistage carcinogenesis, we have studied the mode of ODC induction in Syrian-hamster-embryo(SHE) cells stage-exposed to carcinogens and to non-carcinogens. One-stage (5 hr) treatment of SHE cells with 50 microM clofibrate (CLF), a non-genotoxic carcinogen, or with 0.4 microM benzo(a)pyrene (BaP), a genotoxic carcinogen, slightly decreased basal ODC activity. Using the 2-stage exposure, 1 hr to carcinogen, then replacement by TPA for 5 hr, the ODC activity was higher than that obtained with TPA alone. This ODC superinduction was not observed when SHE cells were similarly pre-treated with non-carcinogenic compounds. Several environmental chemicals, pesticides, solvents, oxidizers and drugs were investigated with this SHE cell model. With one-stage exposure, some xenobiotics decreased basal ODC activity, while for others ODC changes were not noticeable. With 2-stage exposure (chemical followed by TPA), all carcinogens amplified the TPA-inducing effect, resulting in ODC superinduction. Comparative studies of the action of carcinogens and of non-carcinogens, using 2-stage exposure protocols, clearly show a close relationship between ODC induction rate and morphological transformation frequency.     

Antithymocyte globulin for patients with myelodysplastic syndrome

Twenty-five transfusion-dependent myelodysplastic syndrome (MDS) patients (with < 20% blasts) were treated in a phase II study with antithymocyte globulin (ATG) at 40 mg/kg/d for four doses and then followed with blood counts every 2 weeks and clinic visits every 3 months, for a median of 14 months (range 1-38 months). 11 (44%) patients responded and became transfusion-independent after ATG, including three complete responses, six partial responses, and two minimal responses. Responses were observed in 9/14 patients (64%) with refractory anaemia (RA) and 2/6 patients (33%) with refractory anaemia with excess blasts (RAEB). Median response duration was 10 months (range 3-38 months). The Kaplan-Meier estimate of overall survival was 84% at 38 months, with one early death due to pneumonia and two deaths from disease progression to leukaemia. Side-effects consisted mainly of mild serum sickness in all patients. A single course of ATG restored haemopoiesis in some patients with MDS and was well tolerated.