A.R Mueller

Liver transplantation for alcoholic cirrhosis.

Abstract 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 patients or relatives 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

Abstract 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 appearence. 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.

Management of acute steroid-resistant rejection after liver transplantation.

Abstract. Prior to the FK506 era, OKT3 was primarily used for treatment of steroid-resistant rejection. Initially FK506 has been used as a last treatment of refractory acute or chronic rejection. We provide strong evidence that the use of FK506 is more successful if rescue therapy is performed early instead of using it as the last resort. Between September 1988 and March 1995 a total of 600 liver transplantations were performed in 550 patients. Of these 550 patients, 426 received primarily cyclosporine A (CsA)-based immunosuppression. Of the 426 CsA patients, 70 (16.4%) required either FK506 (51.4%), or OKT3 rescue therapy (27.1%), or a combination of the two drugs (21.5%). The latter group of patients received first OKT3 and then FK506 rescue when OKT3 therapy failed. Treatment was initiated simultaneously (within 1 week) in 11 patients, and 4 patients received FK506 rescue later during the course of rejection. The highest success rates (88.9%) were observed in patients given FK506 rescue therapy. Retransplantation was necessary more often in patients receiving OKT3 than in those with FK506 rescue therapy (15.8% versus 5.5%, respectively). Retransplantation and death due to chronic rejection increased with the need for additional FK506 rescue therapy after OKT3 failure. This increase was most pronounced in patients receiving FK506 during the late course of rejection, reaching a failure rate of 75.0% (50.0% of deaths were due to chronic rejection). The lowest incidence of cytomegalovirus infection and of infectious, neurologic, and renal complications was observed in the FK506 rescue group. We conclude that early FK506 rescue therapy may be the treatment of choice for acute steroid-resistant rejection.

FK 506 and mycofenolate mofetil rescue for acute steroid-resistant and chronic rejection after liver transplantation

F K 506 is a potent immunosuppressive agent for prevention and reversal of acute steroid-resistant and early chronic rejection following liver transplantation.‘,’ We and others1-4 have reported a decreased incidence of chronic rejection in FK 506-treated patients. However, there is still a small group of FK 506-treated patients who will develop acute steroid-resistant or early chronic rejection. In fact, chronic rejection has been reported to be responsible for at least 20% of graft failures following liver transplantation.5 FK 506 has been shown very effective for suppression of T-cell-mediated immune response, but less effective in suppressing the humoral B-cell-mediated response. Therefore, the combination of FK 506 with a B-cell suppressive immunosuppressant like mycofenolate mofetil (MMF) may be of advantage. In the present study, we analyzed the outcome of patients developing acute steroid-resistant and chronic rejection with respect to the kind of rescue treatment.

Searching for the optimal management of hepatitis C patients after liver transplantation

Abstract The optimal immunosuppressive regimen in patients transplanted for hepatitis C (HCV) is still under discussion. High immunosuppression may promote viral replication and recurrent graft hepatitis. But acute and chronic rejection frequently seen in conjunction with HCV recurrence may require some rescue therapy. One hundred and thirty‐seven patients transplanted for HCV cirrhosis, who were HCV‐RNA positive prior to transplantation, were analyzed. Seventy‐nine patients received CSA‐based immunosuppression and 58 patients FK506‐based immunosuppression. One‐month patient survival was 100% in both groups. Three month and 1‐year survival rates and the cumulative 1–5‐year patient survival was similar in CsA‐treated [67/79 (84.8%)] and FK506‐treated patients [50/58 (86.2%)]. Re transplantations for HCV recurrence were performed in 5.1% of CsA‐treated patients and 6.9% of FK506‐treated patients; it was successful in 50% and 75% of patients, respectively. Conversion from CsA to FK506 and vice versa was high with 25 out of 79 patients (31.6%) converting in the CsA group and 8 out of 58 patients (13.8%) converting in the FK506 group. Conversion to FK506 was performed due to acute and chronic rejection and to CsA because of toxicity and HCV recurrence. In both groups, 25% of converted patients died. Five patients of the CsA group and 9 of the FK506 group received OKT3; more than one‐third of each group died. Five patients in the CsA group and 6 in the FK506 group received mycophenolate mofetil (MMF) for HCV recurrence or acute and chronic rejection in conjunction with HCV recurrence. All patients of this critical group are alive with good graft function. In conclusion, survival rates of HCV patients were similar to those seen for other indications. Conversion from CsA to FK506 and vice versa was high and reflects a critical group concerning patient survival. OKT3 treatment should be avoided. A promising therapeutic option for critical patients experiencing acute or chronic rejection in conjunction with HCV recurrence may be treatment with MMF.

Changes at the extracellular matrix during acute and chronic rejection in human liver transplantation.

Abstract We have previously observed changes at the extracellular matrix (ECM) which significantly correlated with the extent of preservation and reperfusion injury. In the present study, we attempted to investigate whether the ECM may be also involved in the pathophysiological sequelae of acute and chronic rejection. Of 81 patients monitored for the ECM parameters laminin, hyaluronic acid, fibronectin receptor, and transforming growth factor (TGF)‐β 28 patients developed acute rejection (<1 month), in 14 patients (17.4%) acute rejection was steroid resistant, 4 patients (4.5 %) developed early chronic rejection following acute steroiD‐resistant rejection. Acute and chronic rejection were confirmed by established clinical and histological criteria. Laminin levels were significantly increased in patients experiencing acute steroiD‐resistant rejection (4204 ± 133 ng/ml; P≤ 0.01) compared with patients with steroiD‐sensitive rejection (1059 ± 27.3 ng/ml) and with an uneventful postoperative course (1214 ± 17.4 ng/ml). No increase in laminin was observed in those four patients who developed early chronic rejection (1099 ± 58.7 ng/ml). Hyaluronic acid, fibronectin receptor, and TGF‐β levels also increased in patients with acute steroiD‐resistant rejection; hyaluronic acid: 290 ± 10.8 μg/1 vs 154 ± 13.6 μg/1 and 131 ± 11.7 μg/1 in patients with steroiD‐sensitive and no rejection, respectively; fibronectin receptor: 1003 ± 23.5 ng/ml vs 573 ± 24.8 ng/ml and 428 ± 13.6 ng/ml in patients with steroiD‐sensitive and no rejection, respectively; and TGF‐β: 393 ± 14.9 pg/ml versus 315 ± 10.7 pg/ml and 233 ± 8.9 pg/ml in patients with steroiD‐sensitive and no rejection, respectively. A further increase in hyaluronic acid levels was observed in patients who developed early chronic rejection, while fibronectin receptor and TGF‐β levels remained low, similarly to laminin levels. The increase in laminin, hyaluronic acid, fibronectin receptor, and TGF‐β during acute steroiD‐resistant rejection may be stimulated by the rejection‐related release of cytokines and adhesion molecules which paralleled the increase in ECM parameters. The lack of increase in laminin and fibronectin receptor levels in those patients who developed early chronic rejection may reflect an inability to recover from acute rejection.

Cytokine pattern in patients with infections after liver transplantation

Severe infections are the most frequent cause of death after liver transplantation. Determination of new parameters may increase the knowledge of pathophysiological mechanisms of infection. For this purpose, 81 patients with 85 liver transplants were monitored for various new parameters on a daily basis. Patients with severe infections (n = 10) were compared with patients with mild or asymptomatic cholangitis (n = 11) and with patients with an uneventful postoperative course (n = 37). One-year patient survival was 88.9%; in five patients, death was related to serious infections. Mean neopterin, soluble tumor necrosis factor-RII (sTNF-RII), and hyaluronic acid levels were significantly elevated in patients with serious infections compared with the other two groups (P < or = 0.01). A further increase in sTNF-RII and neopterin levels was observed in patients with lethal infections (P < or = 0.01 versus surviving patients with serious infection). An increase in neopterin levels was observed prior to severe infection, and in six of ten patients, this increase occurred as early as during the reperfusion period. Soluble TNF-RII and hyaluronic acid levels also increased significantly prior to severe infection. Interleukin (IL)-6, soluble intercellular adhesion molecule-1 (sICAM-1), and sIL-2R increased in patients with serious infection and cholangitis to a similar extent. As part of an overwhelming immune response, a significant increase in IL-6, sIL-2R, and also IL-1 beta levels occurred during the late phase of lethal infection (P < or = 0.01 versus surviving patients with serious infection). Routine monitoring of these parameters may improve current diagnostic tools and possibly lead to earlier detection of patients at risk after liver transplantation.

Clinical small bowel transplantation: Focus on mucosal barrier function

RECENTLY SMALL BOWEL transplantation has evolved to an established treatment for patients with short gut syndrome and intestinal failure. The introduction of new immunosuppressants offer the opportunity to minimize acute rejection episodes and associated problems. Nevertheless, good initial graft function with maintainance of the mucosal barrier function are of great importance. Preservation/reperfusion injury impairs mucosal barrier function and furthermore initiates the release of mediators. The release of specific and nonspecific inflammatory mediators may promote serious postoperative complications including the development of infection and acute rejection. Therefore, new strategies are required to decrease reperfusion injury and restore mucosal barrier function. Early postoperative enteral nutrition has been shown to restore mucosal barrier function and to decrease the incidence of infection including pneumonia, peritonitis, and sepsis. Enteral preparations containing glutamine, arginine, and omega-3 fatty acids, so called immunonutritions, are known to decrease the release of cytokines, reactive oxygen intermediates, and other mediators in critically ill patients. Lactobacilli, naturally found in the small intestine, have been shown to prevent bacterial overgrowth, to restore gut barrier function, and thereby, to reduce the occurrence of infection. To decrease infectious complications and possibly rejection, donors and recipients of small bowel grafts were treated with lactobacilli and immunonutrition.

Monitoring of immunosuppression after clinical small bowel transplantation

ACUTE REJECTION (AR) remains the most prominent risk factor following small bowel transplantation. Despite improved patient and organ survival rates from approximately 50% to 97% and 71%, respectively, by switching immunosuppression from cyclosporine (CsA)based protocols to tacrolimus (Tac)-based regimens, the rejection rate remains as high as 95% with 60% of rejection episodes occurring in the initial 3 months. New potent immunosuppressants, such as rapamycin (Rapa) and monoclonal antibodies against IL-2 receptor (daclizumab [Dac]), are believed to have the potential to further decrease rejection rates and improve outcomes after small bowel transplantation (SBTx). Pinna et al compared different induction protocols, including cyclophosphamide, mycophenolate mofetil, OKT3, and Dac, with Dac resulting in slightly decreased rejection rates and fewer infectious complications. Abu-Elmagd et al presented preliminary data suggesting the efficacy of Dac as induction therapy together with a Tac-based immunosuppressive regimen to reduce acute rejection (AR) rates (by 43%). The incidence rate of viral infection for and posttransplant lymphoproliferative disease was 7% for each. The impact of additional to Tac-based protocols of Rapa, steroids, and Dac induction therapy is undergoing evaluation in terms of whether they decrease the AR rate while increasing the risk for development of immunosuppression-associated infections, including CMV and EBV. However, monitoring of immunosuppression may facilitate individualized rather than fixed dosing of induction therapy with Dac.

Hepatitis C: Indication for anti-viral therapy?

Abstract  Hepatitis C infection is a frequent indication for liver transplantation. In general, recurrent graft hepatitis is assumed to be mild, but may be the cause of lethal postoperative complications in a small patient population. Out of 500 transplants in 458 patients, 123 patients were transplanted due to hepatitis C infection (26.7 %) between September 1988 and April 1994. Cumulative 1– to 6‐year patient survival was similar for patients transplanted due to hepatitis C (87.0 %) and those transplanted for other indications (86.0 %). In patients with hepatitis C virus (HCV), death, in 50 % of the cases, was related to HCV recurrence and chronic rejection. Four patients (25.0 %) died because of severe infection and multiple organ failure syndrome unrelated to HCV recurrence and chronic rejection. The incidence of retransplantation was similar in HCV (9.8 %) and other patients (8.4 %). In HCV patients, 6 of 12 retransplantations (50.0 %) were performed due to HCV recurrence and chronic rejection. Of 123 HCV patients, 45 experienced histo‐logically proven recurrent graft hepatitis between 2 weeks and 5.5 years after transplantation. The incidence of acute rejection was similar in both groups. The incidence of steroid‐resistant rejection was, however, higher in HCV patients (29.3 %) than in those transplanted for other indications (14.5 %; P ≤ 0.05). Furthermore, there was a significant association between acute rejection and the development of recurrent graft hepatitis. In conclusion, patients with hepatitis C may be transplanted with as good patient and graft survival rates as patients transplanted for other indications. However, the combination of recurrent graft hepatitis and chronic rejection remains the most limiting factor for some of these patients, which strengthens the necces‐sity for a specific anti‐viral therapy.