IL-2 antagonists: the European perspective.

Acute rejection remains the main risk factor following intestinal transplantation. New immunosuppressive agents have substantially reduced the incidence of severe acute rejection. The question arises, which is the most powerful immunosuppressive combination with the lowest incidence of side effects? According to International Intestinal Transplant Registry data, anti-IL-2 antibodies are slightly advantageous compared with antilymphocyte preparations with respect to long-term patient survival. However, different antilymphocyte preparations are used in different doses and at different time points. The anti-IL-2 antibodies daclizumab and basiliximab were also used in different protocols. Therefore, final results on efficacy are awaited. The most important difference between IL-2 antibodies and antilymphocyte preparations is the suppression of CD4+ CD25+ T lymphocytes by anti-IL-2 antibodies. Antilymphocyte preparations do not affect CD4+ CD25+ T cells. Because regulatory CD4+ CD25+ T cells are essential for tolerance induction, protocols attempting tolerance may omit anti-IL-2 antibodies in the future.

Isolated adult intestinal transplantation using portal venous drainage.

There is some evidence that portal venous drainage may offer immunologic and metabolic advantages in small bowel transplantation. Isolated small bowel transplantation was performed in 14 adult patients. In all cases, the donor pancreas was transplanted into another patient. During the donor procedure, the superior mesenteric artery and vein were separated below the division of the inferior pancreaticoduodenal artery and below the veins of the pancreatic head. An arterial interposition graft was used in all cases. One donor mesenteric artery was reconstructed in 6 patients; two arteries in 5 patients; and three arteries in 3 patients. Proximal arteries of the graft were ligated and the upper part of the jejunum resected. In 10 patients, a direct anastomosis was performed in an end-to side fashion between donor superior mesenteric vein (SMV) and recipient inferior mesenteric vein (IMV). In 2 patients, a branch of the superior mesenteric vein was used and 2 patients required a venous interposition graft to confluence using the donor iliac vein. Patency of the venous anastomosis was documented by magnetic resonance imaging (MRI) angiography after 6 months. No vascular complications have been observed to date. Portal venous drainage is technically feasible in most cases. An anastomosis to the recipient IMV offers the advantage of being direct despite the short donor vein segment. Furthermore, donor and recipient vessels are well matched for size. Using microsurgical techniques, vascular complications may be avoided.

Immunosuppression following intestinal transplantation.

Acute rejection is still the main risk factor following intestinal transplantation. Potent immunosuppression decreases rejection frequency, but may increase immunosuppression-related complications. Isolated small intestinal transplantation was performed in 14 adult patients with short bowel syndromes. Immunosuppression included tacrolimus and rapamycin in combination with steroids for 6 months after ATG or daclizumab induction therapy. In addition to protocol biopsies, cellular immune status and soluble immune parameters were used to guide immunosuppression. CMV and EBV markers were determined on a routine basis. Ten of 14 patients (71%) survived for 1 to 38 months (median 26 months). Eight patients are at home, in good physical condition, completely on enteral nutrition. Among the 5 patients (36%) who developed acute rejection, 2 patients with early postoperative events underwent graft removal and 1 patient died due to multiple organ failure. Two patients developed severe acute rejection episodes at 10 and 24 months following transplantation. Both patients recovered following OKT3 rescue therapy and increased baseline immunosuppression with repeated methylprednisolone and infliximab treatment. Infections included peritonitis (n = 3), pneumonia (n = 3), central line infection (n = 5), urinary tract (n = 2), CMV (n = 2), and EBV (n = 4). Two patients developed anastomotic leaks at the esophageal and coloanal anastomosis. In conclusion, acute rejection episodes can be controlled by potent immunosuppression using tacrolimus in combination with rapamycin. Immunosuppression-associated complications, including infections, were in an acceptable range. However, even late after transplantation, reduction in immunosuppression may lead to severe rejection without major clinical symptoms.

Management of venous access problems before and after intestinal transplantation: case reports.

Patients suffering irreversible loss of intestinal function require total parenteral nutrition (TPN). During long-term TPN, catheter infections are a common problem and intestinal transplantation (ITx) is indicated when patients experience loss of venous access. We report two patients with short bowel syndrome--one before and one after ITx. The patient listed for ITx had several catheter infections with septic temperatures. Staphylococcus aureus, detected in blood cultures, was treated with vancomycin. Packing of the central venous line (CVL) with vancomycin was not successful; the CVL was changed. Search for an infectious focus identified a septic femoral head destruction that was treated by incision and implantation of a hip endoprothesis. Thereafter, the patient was free from infection. The second patient underwent ITx on January 2, 2003, and is free from TPN. ITx was complicated by temporary acute renal failure and heparin-induced thrombocytopenia (HIT) syndrome. After compensation of kidney function, the patient required additional saline solution (1 to 2 L/d) to optimize renal perfusion. A CVL was placed in the external iliac vein (EIV) due to previous loss of venous access. At 2 months after ITx, the CVL was infected and the patient was septic. MR scan revealed only one jugular vein to provide vascular access. Therefore, the CVL was changed from the right to the left EIV. Postoperatively, the patient developed thrombosis of right iliac vein and a wound infection that is probably related to the nearby graft ileostomy. At present, the patient is in good condition with a functioning graft. In conclusion, recurrent CVL infections before ITx might reflect other infectious foci that require intensive diagnostic evaluation. After ITx, CVL infection may cause venous thrombosis. Therefore, a single upper venous access should be preserved for optimal care.

[Small bowel transplantation - current status and initial results]. / Dünndarmtransplantation - aktueller Stand und eigene Ergebnisse.

During the last years, clinical small bowel transplantation has significantly improved. This is especially true for isolated small bowel transplantation with success rates of 80 % 1-year patient survival. Currently, approximately 100 small bowel transplantations are performed per year worldwide. In Germany, small bowel transplantation is still rare, because of the high risk for the development of acute rejection and rejection-associated complications. This includes peritonitis and sepsis as well as over-immunosuppression-associated infections. Due to improvements in immunosuppression, the incidence of acute rejection decreased from about 85 % below 25 %. Half of the patients will receive a combined liver-small bowel graft due to TPN (total parenteral nutrition)-associated liver cirrhosis. Although the combined procedure has immunological advantages, complication rates are high and patient survival is significantly lower (ca. 50 % at 1 year). Next to bacterial, fungal, and atypic infections, which are frequently associated with rejection and other complications, CMV and EBV infections are of significant interest. This is of special importance for EBV infections, since all PTLD (lymphoproliferative disease) after small bowel transplantation are EBV-associated so far. Viral infections should be monitored and preemptive therapy using ganciclovir or foscavir will be initiated. Of the 800 patients transplanted so far, 50 % are still alive up to 15 years. Of these, more than 80 % are off parenteral nutrition, in good healths, with good quality of live.

Liver transplantation for alcoholic cirrhosis.

Because of the donor shortage, there are concerns for liver transplantation in patients with alcoholic cirrhosis. We therefore analyzed patients transplanted for alcoholic cirrhosis at our center with respect to patient and graft survival, recurrence of disease, and postoperative complications. Out of 1000 liver transplantations performed in 911 patients, 167 patients were transplanted for alcoholic cirrhosis; 91 patients received CsA- and 76 patients FK506-based immunosuppression. Recurrence was diagnosed by patient's or relative's declaration, blood alcohol determination, and delirium. Diagnosis and treatment of acute and chronic rejection was performed as previously described. One- (96.8% versus 91.3%) and 9-year patient survival (83.3% versus 80%) compared well with other indications. Five of 15 patients died due to disease recurrence. Recurrence of disease was significantly related to the duration of alcohol abstinence prior to transplantation. In patients who were abstinent for less than 6 months (17.1%), recurrence rate was 65%, including four of the five patients who died of recurrence. Recurrence rate decreased to 11.8%, when abstinence time was 6-12 months and to 5.5%, when the abstinence times was > 2 years. Next to duration of abstinence, alcohol relapse was significantly related to sex, social environment, and psychological stability. The incidence of acute rejection compared well with other indications (38.1%); CsA: 40.1% versus 33.3% in FK506 patients. In all, 18.2% of CsA patients experienced steroid-resistant rejection compared with 2.6% of FK506 patients. Seven patients (7.6%) in the CsA group and one patient (1.3%) in the FK506 group developed chronic rejection. A total of 57.1% developed infections; 5.7% were life-threatening. CMV infections were observed in 14.3% (versus 25% for other indications). New onset of insulin-dependent diabetes was observed in 8.6% and hypertension in 32.4%. In conclusion, alcoholic cirrhosis is a good indication for liver transplantation with respect to graft and patient survival and development of postoperative complications. FK506 therapy was favourable to CsA treatment. Patient selection is a major issue and established criteria should be strictly adhered to. Patients with alcohol abstinence times shorter than 6 months should be excluded, since recurrence and death due to recurrence was markedly increased in this group of patients.

Perioperative factors influencing patient outcome after liver transplantation.

We have previously shown that the development of multiple organ dysfunction syndrome (MODS) after liver transplantation significantly reduced patient survival. Therefore, the question arises of which are the most prominent perioperative donor and recipient factors leading to MODS after transplantation. In total, 634 patients with 700 liver transplants were analyzed. Donor factors included age, increase in transaminases, sex mismatch, requirement for catecholamines, intensive care time, histology, and macroscopic graft appearance. Recipient factors included Child classification, preoperative gastrointestinal (GI) bleeding, mechanical ventilation, hemodialysis, and requirement for catecholamines. MODS was defined by more than two severe organ dysfunctions. The cumulative 2 to 9-year patient survival was 90.9% in patients developing less than 3 severe organ dysfunctions following transplantation. Survival decreased to 60.3% in patients with MODS. Neither any of the donor factors nor the duration of cold ischemia (CIT) was associated with an increase in MODS or decrease in survival. On the other hand, duration of warm ischemia, amount of blood loss, requirement for red packed blood cells, and reoperation had an influence on the development of MODS (40%-56%) and decreased patient survival to 58%-69%. Preoperative therapy with catecholamines, GI bleeding, mechanical ventilation, and hemodialysis were associated with the development of MODS in 54%-88%. Patient survival following MODS decreased to 50%-74%. Initial graft function had a slight influence on the development of MODS, but no influence on the long-term patient survival. In conclusion, patient survival was significantly influenced by the development of postoperative MODS. The most prominent factors in this were recipient and intraoperative ones. No major influence was observed for donor factors, CIT, and initial graft function. Prevention of MODS will further improve the outcome after liver transplantation.

[Therapy of recurrent hepatitis B infection after liver transplantation. A retrospective analysis of 200 liver transplantations based on hepatitis B associated liver diseases]. / Therapie der rekurrenten Hepatitis-B-Infektion nach Lebertransplantation. Eine retrospektive Analyse von 200 Lebertransplantationen aufgrund von Hepatitis-B-assoziierten Lebererkrankungen.

BACKGROUND: Before introduction of passive immunoprophylaxis and new antiviral nucleoside analogues the course of hepatitis B recurrence after liver transplantation could hardly be influenced. The result was a inferior graft survival. In the present retrospective analysis of the efficacy of hepatitis B therapy after liver transplantation was analysed retrospectively. PATIENTS AND METHODS: Between 1988 and 1998 in total 179 patients were transplanted due to hepatitis B related liver failure at our centre. All patients received passive immunoprophylaxis with hepatitis B immunoglobulin. In case of reinfection after 1993 an antiviral therapy with famciclovir 1500 mg daily was initiated (n = 26), since 1996 lamivudine (100-150 mg daily) was used (n = 12). In case of viral breakthrough under famciclovir treatment or prophylaxis therapy was switched to lamivudine (n = 22). In case of ineffectiveness of lamivudine an antiviral combination therapy with lamivudine and interferon (n = 4) or lamivudine and famciclovir (n = 4) was initiated. Before availability of antiviral agents or in case of viral breakthrough in total 12 patients were retransplanted due to acute or chronic reinfection. RESULTS: With passive immunoprophylaxis reinfection rate was 33%, 43% and 44% after 1, 3 and 5 years respectively. Without antiviral treatment 52% of patients died within the first year after reinfection. Antiviral therapy with lamivudine or famciclovir improved the one year survival after reinfection to 79%. Suppression of viral replication was more effective with lamivudine. Under lamivudine 26 patients (76%) became HBV-DNA negative, 9 patients HBsAg negative (26%). In contrast no patient became HBsAg negative during famciclovir therapy. Lamivudine was effective also after famciclovir breakthrough in 94% of patients. In case of lamivudine resistant reinfection viral replication could be suppressed with an antiviral combination therapy up to negative HBV-DNA in the hybridization assay. Severe side effects were not observed during any of the antiviral therapies. The graft survival after retransplantation for hepatitis B reinfection was 42% and 25% after one and 3 years. CONCLUSION: Whereas it is generally accepted, that passive immunoprophylaxis lowers the reinfection rate it could be shown in the present study, that antiviral treatment lowers mortality of hepatitis B reinfection. The major problem of lamivudine and famciclovir is viral resistance formation. In this case an antiviral combination therapy might be useful, whereas retransplantation for hepatitis B reinfection should be considered carefully due to inferior graft survival rates.