Bruno Gridelli

Epstein-Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant.

BACKGROUND Solid organ transplant patients undergoing long-term immunosuppression have high risk of developing lymphomas. The pathogenesis of the late-occurring posttransplantation lymphoproliferative disorders (PTLD) have not yet been extensively investigated. METHODS We studied 15 patients who developed PTLD after a median of 79 months (range 22-156 months) after organ transplant. Clonality, presence of Epstein-Barr virus (EBV) genome, and genetic lesions were evaluated by Southern blot analysis or polymerase chain reaction. RESULTS All monomorphic PTLD and two of three polymorphic PTLD showed a monoclonal pattern. Overall, 44% of samples demonstrated the presence of the EBV genome. Within monomorphic PTLD, the EBV-positive lymphomas were even lower (31%). A c-myc gene rearrangement was found in two cases (13%), whereas none of the 15 samples so far investigated showed bcl-1, bcl-2, or bcl-6 rearrangement. The modulation of immunosuppression was ineffective in all patients with monomorphic PTLD independent of the presence of the EBV genome. The clinical outcome after chemotherapy was poor because of infectious complications and resistant disease. With a median follow-up of 4 months, the median survival time of these patients was 7 months. CONCLUSIONS Late occurring lymphomas could be considered an entity distinct from PTLD, occurring within 1 year of transplant, because they show a histological and clinical presentation similar to lymphomas of immunocompetent subjects, are frequently negative for the EBV genome, are invariably clonal, and may rearrange the c-myc oncogene. New therapeutic strategies are required to reduce the mortality rate, and new modalities of long-lasting immunosuppression are called for.

Short- and long-term effects of the transjugular intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis

Background and aims Portal vein thrombosis (PVT) negatively impacts the prognosis in patients with cirrhosis. The aim of our study was to evaluate the effects of transjugular intrahepatic portosystemic shunt (TIPS) placement in patients with cirrhosis complicated by PVT. Methods Seventy consecutive cirrhotic patients with non-tumoural PVT treated with TIPS for portal hypertension complications from January 2003 to February 2010 in a tertiary-care centre were followed until last clinical evaluation, liver transplantation, or death. Results TIPS was successfully placed without major procedure-related complications. After TIPS, the portal venous system was completely recanalised in 57% of patients, a marked decrease in thrombosis was observed in 30%, and no improvement was seen in 13%. 95% of patients with complete recanalisation after TIPS maintained a patent portal vein. Predictors of complete recanalisation were a less severe and extensive PVT, de novo diagnosis of PVT, and absence of gastro-oesophageal varices. At follow-up, 1 patient had recurrence of bleeding, and 2 had spontaneous bacterial peritonitis. The rate of TIPS dysfunction at 12 and 24 months was 38% and 85% for bare stent and 21% and 29% for covered stent (p=0.001), respectively. Occurrence of encephalopathy at 12 and 24 months was 27% and 32%, respectively. Fifteen patients underwent liver transplantation. Survival at 1, 12 and 24 months was 99%, 89% and 81%, respectively. Conclusion Long-term outcome of non-tumoural PVT in patients with cirrhosis treated with TIPS placement is excellent. Prospective randomised studies should investigate whether TIPS placement is the best therapeutic option in patients with cirrhosis who develops non-tumoural PVT.

Combined kidney and liver transplantation for familial haemolytic uraemic syndrome.

Recurrent haemolytic uraemic syndrome (HUS) is a genetic form of thrombotic microangiopathy that is mostly associated with low activity of complement factor H. The disorder usually develops in families, leads to end stage renal disease, and invariably recurs after kidney transplantation. We did a simultaneous kidney and liver transplantation in a 2-year-old child with HUS and a mutation in complement factor H to restore the defective factor H, with no recurrence of the disease. The operation was successful, and at discharge, the child had healthy kidney and liver function, with no sign of haemolysis.

Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor h gene mutation.

Factor H‐associated hemolytic uremic syndrome (HUS) is a genetic form of thrombotic microangiopathy characterized by deficient factor H (HF‐1) levels/activity and uncontrolled complement activation. The disorder mostly leads to end‐stage renal disease and often recurs after kidney transplantation. We previously demonstrated that in a child with HF‐1‐associated HUS a simultaneous kidney and liver transplantation restored the defective HF‐1 with no recurrence of the disease in the transplanted kidney.

Corticosteroid‐free immunosuppression with tacrolimus following induction with daclizumab: A large randomized clinical study

This open, randomized (1 : 1), multicenter, 3‐month study compared a dual tacrolimus plus steroids (Tac / steroids) regimen with a steroid‐free immunosuppressive regimen of tacrolimus following daclizumab induction therapy (Tac / Dac) in adult liver transplant recipients. The full analysis set comprised 347 patients in the Tac / steroids group and 351 in the Tac / Dac group. Mean tacrolimus dose during month 3 was 0.11 mg/kg/day in both groups; mean whole‐blood trough levels during month 3 were 10.9 ng/mL (Tac / steroids) and 10.6 ng/mL (Tac / Dac). The incidence of biopsy‐confirmed acute rejection that required treatment was similar in both groups: 26.5% in the Tac / steroids group and 25.4% in the Tac / Dac group (P = .727). However, the incidence of biopsy‐confirmed corticosteroid‐resistant acute rejection was higher in the Tac / steroids group than in the Tac / Dac group (6.3 vs. 2.8%; P = .027). Kaplan‐Meier estimates of graft survival (92.2 vs. 90.5%) and patient survival (94.5 vs. 93.7%) were similar in both groups. While also the overall adverse event profiles were similar, the incidences of diabetes mellitus (15.3 vs. 5.7%, respectively; P < .001) and cytomegalovirus infection (11.5 vs. 5.1%, respectively; P = .002) were higher in the Tac / steroids group compared with the Tac / Dac group. Mean cholesterol levels increased by 16% in the Tac / steroids group, but were unchanged in the Tac / Dac group during the study. In conclusion, tacrolimus monotherapy following daclizumab induction is an effective and safe regimen, with an advantage over concomitant steroid‐maintenance therapy in terms of a lower incidence of diabetes and viral infection, and a lower incidence of steroid‐resistant acute rejection. (Liver Transpl 2005;11:61–67.)

Efficacy and Safety of Fully Covered Self- Expandable Metallic Stents in Biliary Complications After Liver Transplantation: A Preliminary Study

After liver transplantation, the most common biliary complication is the anastomotic stricture, which is followed by biliary leakage. Studies have focused on the endoscopic treatment of biliary complications in transplanted patients with duct‐to‐duct reconstruction, showing a success rate of 70% to 80% after orthotopic liver transplantation and of 60% after living‐related liver transplantation. Once the endoscopic approach fails, surgical treatment with a Roux‐en‐Y choledochojejunostomy is the sole alternative treatment. The aim of this prospective observational study was to analyze the efficacy and safety of fully covered self‐expandable metallic stents for the treatment of posttransplant biliary stenosis and leaks in patients in whom conventional endoscopic retrograde cholangiopancreatography (ERCP) failed. From January 2008 to January 2009, 16 patients met the criteria of endoscopic treatment failure, and instead of surgery, a fully covered stent was placed. All patients had at least 6 months of follow‐up (mean follow‐up of 10 months). After removal, 14 patients showed immediate resolution of both the biliary stenosis and leak. After a mean of 10 months of follow‐up, only 1 patient showed biliary stenosis recurrence. No major complications occurred in any of the patients, except for stent migration in 6 patients, although these presented with no clinical consequences. In conclusion, in patients not responding to standard endoscopic treatment, the placement of fully covered metal stents is a valid alternative to surgery. A cost analysis should be performed in order to evaluate whether to treat transplanted patients suffering from biliary complications with covered self‐expandable metallic stent placement as first‐line therapy. Liver Transpl 15:1493–1498, 2009.

Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine in children undergoing liver transplantation: randomised European multicentre trial.

BACKGROUND Results of studies in adult recipients of liver allograft suggest that tacrolimus is more efficacious than ciclosporin microemulsion in the prevention of acute rejection. We aimed to compare these drugs in children undergoing liver transplantation. METHODS This 12-month multicentre, open-label, parallel-group, randomised study compared a dual tacrolimus regimen (tacrolimus/corticosteroids, n=93) with a triple ciclosporin microemulsion regimen (ciclosporin microemulsion/corticosteroids/azathioprine, n=92) in children who had had liver transplants (age < or =16 years, bodyweight < or =40 kg). Initial oral daily doses were 0.30 mg/kg for tacrolimus and 10 mg/kg for ciclosporin microemulsion. Primary endpoint was the incidence of and time to first histologically proven acute rejection. We excluded patients from analysis if they did not receive the study drug, or were given incorrect medication. Otherwise patients were analysed in accordance with their random treatment allocation, irrespective of whether they switched medication during the trial. FINDINGS Median age was 22 months (IQR 9-56) in the tacrolimus group and 17 months (9-54) in the ciclosporin microemulsion group. We noted no difference between treatment groups with respect to patient survival (93.4% vs 92.2%; p=0.77) or graft survival (92.3% vs 85.4%; p=0.16) at month 12 after transplant. The acute rejection free rate at study end (Kaplan-Meier method) was 55.5% for patients on tacrolimus and 40.2% for patients on ciclosporin microemulsion (p=0.0288). The Kaplan-Meier estimate of patients free from corticosteroid-resistant acute rejection at study end was 94.0% for tacrolimus-treated patients and 70.4% for ciclosporin-microemulsion-treated patients (p<0.0001). Overall, incidence of adverse events did not differ between groups. INTERPRETATION Tacrolimus is a safe and effective treatment for the prevention of rejection after liver transplantation in children.

Split-liver transplantation eliminates the need for living-donor liver transplantation in children with end-stage cholestatic liver disease.

Background. End-stage cholestatic liver disease (ESCLD) is the main indication for liver replacement in children. Pediatric cadaver–organ-donor shortage has prompted the most important evolutions in the technique of liver transplantation, in particular living-donor liver transplantation (LDLT) and split-liver transplantation (SLT). Methods. Between November 1997 and June 2001, 127 children with ESCLD were evaluated for liver transplantation, and 124 underwent 138 liver transplantations after a median time of 40 days. Causes of liver disease were congenital biliary atresia (n=96), Alagille’s syndrome (n=12), Byler’s disease (n=8), and other cholestatic diseases (n=8). Results. Ninety (73%) patients received a split-liver graft, 28 (23%) a whole liver, and 6 (4%) a reduced-size liver. Overall 2- and 4-year patient survival rates were 93% and 91%, respectively; the 2- and 4-year graft-survival rates were 84% and 80%, respectively. In split-liver recipients, 4-year patient and graft-survival rates were 91% and 83%, respectively; these were 93% and 78%, respectively, in whole-liver recipients and 67% and 63%, respectively, in reduced-size liver recipients. Retransplantation rate was 11%, whereas mortality rate was 8%. Overall incidence of vascular and biliary complication were 16% and 27%, respectively. Conclusions. SLT can provide liver grafts for children with ESCLD with an outcome similar to the one reported following LDLT, eliminating mortality while they are on a transplantation wait list. The need for pediatric LDLT should be reevaluated and programs of SLT strongly encouraged and supported at a national and international level.

Impact of Thrombocytopenia on Survival of Baboons with Genetically Modified Pig Liver Transplants: Clinical Relevance

A lack of deceased human donor livers leads to a significant mortality in patients with acute‐on‐chronic or acute (fulminant) liver failure or with primary nonfunction of an allograft. Genetically engineered pigs could provide livers that might bridge the patient to allotransplantation. Orthotopic liver transplantation in baboons using livers from α1,3‐galactosyltransferase gene‐knockout (GTKO) pigs (n = 2) or from GTKO pigs transgenic for CD46 (n = 8) were carried out with a clinically acceptable immunosuppressive regimen. Six of 10 baboons survived for 4–7 days. In all cases, liver function was adequate, as evidenced by tests of detoxification, protein synthesis, complement activity and coagulation parameters. The major problem that prevented more prolonged survival beyond 7 days was a profound thrombocytopenia that developed within 1 h after reperfusion, ultimately resulting in spontaneous hemorrhage at various sites. We postulate that this is associated with the expression of tissue factor on platelets after contact with pig endothelium, resulting in platelet and platelet‐peripheral blood mononuclear cell(s) aggregation and deposition of aggregates in the liver graft, though we were unable to confirm this conclusively. If this problem can be resolved, we would anticipate that a pig liver could provide a period during which a patient in liver failure could be successfully bridged to allotransplantation.

Split and whole liver transplantation outcomes: A comparative cohort study

A specific split liver transplantation (SLT) program has been pursued in the North Italian Transplant program (NITp) since November 1997. After 5 yr, 1,449 liver transplants were performed in 7 transplant centers, using 1,304 cadaveric donors. Whole liver transplantation (WLT) and SLT were performed in 1,126 and 323 cases, respectively. SLTs were performed in situ as 147 left lateral segments (LLS), 154 right trisegment liver (RTL) grafts, and 22 modified split livers (MSL), used for couples of adult recipients. After a median posttransplant follow‐up of 22 months, SLTs achieved a 3‐yr patient and graft survival not significantly different from the entire series of transplants (79.4 and 72.2% vs. 80.6 and 74.9%, respectively). Recipients receiving a WLT or a LLS showed significantly better outcomes than patients receiving RTL and MSL (P < 0.03 for patients and P < 0.04 for graft survival). At the multivariate analysis, donor age of >60 yr, RTL transplant, <50 annual transplants volume, urgent transplantation (United Network for Organ Sharing (UNOS) status I and IIA), ischemia time of >7 hours, and retransplantation were factors independently related to graft failure and to significantly worst patient survival. Right grafts procured from RTL and either split procured as MSL had a similar outcome of marginal whole livers. In conclusion, in 5 yr, the increased number of pediatric transplants due to split liver donation reduced to 3% the in‐list children mortality, and a decrease in the adult patient dropout rate from 27.2 to 16.2% was observed. Such results justify a more widespread adoption of SLT protocols, organizational difficulties not being a limit for the application of such technique. Liver Transpl 12:402–410, 2006.