R. Steffen

Technique and results of biliary reconstruction using side-to-side choledochocholedochostomy in 300 orthotopic liver transplants

ObjectiveThe authors evaluated the complication rate and outcome of side-to-side common bile duct anastomosis after human orthotopic liver transplantation. Summary Background DataEarly and late biliary tract complications after orthotopic liver transplantation remain a serious problem, leading to increased morbidity and mortality. Commonly performed techniques are the end-to-end choledochocholedochostomy and the choledochojejunostomy. Both techniques are known to coincide with a high incidence of leakage and stenosis of the bile duct anastomosis. The side-to-side bile duct anastomosis has been shown experimentally to be superior to the end-to-end anastomosis. The authors present the results of 316 human liver transplants, in which a side-to-side choledochocholedochostomy was performed. MethodsBiliary tract complications of 370 transplants in 340 patients were evaluated. Three hundred patients received primary liver transplants with side-to-side anastomosis of donor and recipient common bile duct. Thirty-two patients with biliary tract pathology received a bilioenteric anastomosis, and in eight patients, side-to-side anastomosis was not performed for various reasons. Clinical and laboratory investigations were carried out at prospectively fixed time points. X-ray cholangiography was performed routinely in all patients on postoperative days (PODs) 5 and 42. In patients with suspected papillary stenosis, endoscopic retrograde cholangioscopy and papillotomy were performed. ResultsOne biliary leakage (0.3%) was observed within the early postoperative period (PODs 0 through 30) after liver transplantation. No stenosis of the common bile duct anastomosis was observed during this time. Late biliary stenosis occurred in two patients (0.6%). T tube-related complications were observed in 4 of 300 primary transplants (1.3%). Complications unrelated to the surgical technique, including papillary stenosis (5.7%) and ischemic-type biliary lesion (3.0%), which must be considered more serious in nature than complications of the anastomosis or T tube-related complications, were observed. Papillary stenosis led to frequent endoscopic interventions and retransplantations in 1.3%.

Comparison Of Quadruple Immunosuppression After Liver Transplantation With Atg Or Il-2 Receptor Antibody

Treatment with monoclonal IL-2 receptor antibodies has been successfully used for immunosuppressive induction therapy following organ transplantation in the recent past. The present study was conducted to compare for the first time a cyclosporine-based quadruple immunosuppressive regimen including a monoclonal IL-2 receptor antibody or ATG as induction therapy after orthotopic liver transplantation. In two groups of 33 patients each, postoperative survival, graft biopsies, liver function enzymes, and the clinical courses after OLT were evaluated. Our results indicate that monoclonal IL-2 receptor antibody therapy as part of a quadruple immunosuppressive regimen is better tolerated and is at least as effective as ATG in prevention of allograft rejection following OLT. Furthermore, our data indicate that a slightly better liver function in general and a lower incidence of rejection reactions necessitating treatment could be observed in the group of patients treated with the monoclonal IL-2 receptor antibody. This study provides evidence that monoclonal IL-2 receptor antibody therapy may be a useful tool for the immunosuppressive induction therapy following clinical orthotopic liver transplantation.

Warm Carolina rinse solution prevents graft failure from storage injury after orthotopic rat liver transplantation with arterialization

Abstract. An injury to nonparenchymal cells, characterized by loss of viability of sinusoidal endothelial cells and activation of Kupffer cells, occurs after reperfusion of livers stored for transplantation. Recently, a new solution, Carolina rinse solution, was shown to prevent reperfusion injury to endothelial cells in vitro almost completely and to improve graft survival after orthotopic rat liver transplantation (ORLT) without arterialization. ORLT with arterialization permits longer cold storage of donor livers and more closely models human surgery. Therefore, we evaluated the effects of Carolina rinse solution on graft survival after ORLT with arterialization in syngeneic Lewis rats. Just prior to implantation, donor livers stored in University of Wisconsin (UW) solution were rinsed with 30 ml of Ringers solution, saline, or Carolina rinse solution at 1d̀‐4d̀C. In livers stored for 15 h and rinsed with Ringers or saline solution, long‐term graft survival was only 8%. Using Carolina rinse solution containing 1 mmol and 200 μmol adenosine per liter, graft survival improved to 40% and 80%, respectively. Graft survival did not improve when using Carolina rinse solution with adenosine omitted or Ringers solution containing 200 μmol adenosine per liter. Livers were also rinsed with Carolina rinse solution containing 200 μmol adenosine per liter at 28d̀‐30d̀C rather than at 1d̀‐4d̀C. With warm Carolina rinse solution, survival improved further to 100%, 80%, and 50% after 15, 18, and 21 h of storage. After 18 h of storage, light and electron microscopy demonstrated marked denudation of the sinusoidal lining and activation of Kupffer cells in grafts rinsed with Ringers solution. Use of Carolina rinse solution greatly improved endothelial structure but did not reduce Kupffer cell activation. In conclusion, these findings show that Carolina rinse solution substantially improves graft survival after ORLT with arterialization. Adenosine and warm temperature are important factors contributing to efficacy. A mechanism of protection appears to be prevention of reperfusion‐induced endothelial cell injury.

Bacterial and fungal colonization and infections using oral selective bowel decontamination in orthotopic liver transplantations

Bacterial and fungal infections are a major cause of morbidity and mortality after orthotopic liver transplantation. In the immunocompromised host, infections are thought to arise from the gut, which is almost always colonized with potential pathogens. Using oral selective bowel decontamination (SBD), potential pathogens can be eradicated from the gut and infections prevented. In this catamnestic study we have reviewed gastrointestinal colonization, bacterial and fungal infections, and bacterial resistance to standard antibiotics in our first 206 liver transplant patients while under SBD. With few exceptions, gram-negatives were eradicated from the gastrointestinal tract and secondary colonization was inhibited. In spite of unsatisfactory elimination of Candida, probably because nystatin doses were too low, Candida infections were rare (n=4) and none was fatal. One and two-year survival rates were 93% and 92%, respectively. The bacterial and fungal infection rate was 27.8% with an infection-related mortality of 1.95%. Infections with aerobic grampositive bacteria prevailed and only 11 gram-negative and 11 fungal infections occurred; among the latter, Aspergillus and Mucor were the most serious and responsible for three of the six deaths in this series. With regard to the development of resistance, we found an increasing number of enterococci and coagulase-negative staphylococci resistant to ciprofloxacin and imipenem, respectively, but unlikely as a consequence of SBD.

Follow-up of recurrent hepatitis B and delta infection in liver allograft recipients after treatment with recombinant interferon-α

Reinfection of the graft with hepatitis B virus (HBV) and hepatitis delta virus (HDV) is a potential complication in patients undergoing orthotopic liver transplantation (OLT). Therefore, we added recombinant interferon-alpha (rIFNa) to the standard immunosuppressive regimen in 11 patients who received transplants following liver failure attributed to cirrhosis B (n = 10, with HDV co-infection in four cases) or fulminant hepatitis B (n = 1). Patients were treated with rIFNa for periods ranging from 2 to 3 months between the first and the 13th month after OLT. All patients received immunosuppressive treatment with low-dose corticosteroids, azathioprine and cyclosporine. Anti-HBs hyperimmune globulin was also administered. None of the patients showed evidence of severe allograft rejection. Seven patients suffered HBV reinfection of the graft with histological signs of acute hepatitis in five cases and transition to chronic hepatitis in one patient. Treatment with rIFNa did not prevent or reduce HBV replication. Reinfection of the graft with HDV was demonstrated by PCR in four patients co-infected with HDV. During treatment with rIFNa liver biopsy specimens from three reinfected patients were transiently negative for HDV antigen but not for HDV RNA, and the sera from two patients were transiently negative for HDV RNA. The data indicate that rIFNa can reduce HDV replication in reinfected liver allografts.

Protection by pentoxifylline against graft failure from storage injury after orthotopic rat liver transplantation with arterialization.

Destruction of the endothelial cell lining and activation of Kupffer cells after reperfusion limits the safe storage of livers for transplantation surgery. Tumor necrosis factor-alpha (TNF) release by activated Kupffer cells may contribute to graft failure from storage injury. Accordingly, we evaluated whether pentoxifylline, which suppresses macrophage TNF release, would improve graft survival after orthotopic rat liver transplantation with arterialization. Livers from syngeneic Lewis rats were stored for 12-24 h in cold UW solution. Prior to implantation, the livers were flushed with cold Ringers solution or warm Carolina rinse solution B. With either rinse, pentoxifylline treatment of graft recipients significantly improved graft survival. Combined use of pentoxifylline (50 mg/kg for 5 days) and Carolina rinse solution doubled the safe storage time to 24 h. Acidotic pH and antioxidants were essential components of Carolina rinse solution that acted synergistically with pentoxifylline. Pentoxifylline was also shown to suppress TNF release by lipopolysaccharide (LPS)-stimulated cultured rat Kupffer cells. Thus, pentoxifylline may protect against primary non-function and failure of grafts from storage injury by suppressing excessive TNF release by activated Kupffer cells. However, neutralization of TNF with excess anti-TNF antibody did not improve survival. This may mean that depletion of TNF is as deleterious as excess TNF production. Alternatively, other Kupffer cell secretions [e.g., interleukin-1 (IL-1), interleukin-6 (IL-6) and other cytokines] may be involved in the pathogenesis of graft failure. In conclusion, pentoxifylline could protect against graft failure from storage injury.

Experience with cuff rearterialization in 600 orthotopic liver grafts in the rat

The model of orthotopic rat liver transplantation has been a useful tool in transplantation research for two decades. Due to technical problems, the optional hepatic artery anastomosis is not performed in many experiments. Recently developed techniques, however, have made rearterialization a simple procedure. With our technique of cuff rearterialization to the recipient common hepatic artery, in 600 rat liver grafts we achieved high viability, and an early patency rate of 100%. Patency rates after 2 and 21 days were nearly 90%. Cuff rearterialization is simple, rapid to perform, and provides a physiologic model. Compared to strictly venous liver grafts, rearterialized grafts demonstrate improvement in survival, more rapid normalization of liver function parameters, a better preserved liver structure, and less biliary complications. Rearterialization is an important component of a physiologically relevant rat liver transplantation model, and non-specific changes due to arterial ischemia may adversely affect the interpretation of experimental data.

Quadruple immunosuppression including a new IL-2-receptor antibody and the incidence of infections after liver transplantation

Immunosuppression is a primary concern after orthotopic liver transplantation (OLT). On the one hand, the graft is at jeopardy through acute or chronic rejection, and on the other, immunosuppression and antirejection therapy increase the risk of infectious complications. Effective immunosuppression therefore should prevent rejections without leading to a high rate of infections, bearing in mind the fact that infections and infection-related complications are the most frequent causes of early death after liver transplantation. With more specific immunosuppression the infectious complications can potentially be minimized. Antithymocyte globulin (ATG) and the first monoclonal antibody OKT3 immunosuppression are non-specific. The replacement of these antibodies in a quadruple immunosuppressive regimen with the new monoclonal IL-2R antibody BT 563 probably reduces the early infection rate. We report on our first experience with BT 563. The incidence of infection was compared with a historical control group with ATG.

Technique of arterial anastomosis in liver transplantation, surgical management in routine situations and anatomical variations.

With a careful donor hepatectomy in order to preserve and, if necessary, to reconstruct accessory liver arteries and a microsurgical technique for the arterial anastomosis the rate of arterial complications after liver transplantation can be kept at a low level.

Multivisceral cluster transplantation in the rat

Transplantation of multivisceral grafts has evolved recently as a new therapeutic modality for hepatopancreatobiliary malignancies. The mutual interactions between the liver, pancreas, small bowel and the recipient organism after cluster grafting are not clearly understood and deserve further experimental evaluation. We present a technique for combined hepatopancreaticoduodenal cluster transplantation in the rat. The cluster grafts consisted of a pancreaticoduodenal graft and an orthotopic arterialized liver graft. A separate arterial anastomosis of the liver and a bile duct anastomosis were not necessary. Bile and exocrine pancreas secretions drained over the duodenal conduit of the graft into the recipients jejunum via an end-to-side anastomosis.