K.-P. Platz

Successful infliximab treatment of steroid and OKT3 refractory acute cellular rejection in two patients after intestinal transplantation

Acute rejection resistant to established immunosuppressive rescue protocols remains the most prominent risk factor after intestinal transplantation. In two patients presenting with steroid-resistant severe acute cellular rejection 9 months and 2 years after intestinal transplantation, complete resolution was not achieved despite 5 and 10 days of OKT3 treatment, respectively, and high-dose triple baseline immunosuppression with tacrolimus, rapamycin, and steroids. There was a dissociated course of rejection with persistent moderate to severe rejection in the terminal portion of the graft despite complete recovery from rejection in the proximal parts. Both patients were treated with four subsequent infusions of infliximab (3 mg/kg body weight), a chimeric anti-tumor necrosis factor-&agr; antibody. There was an immediate response regarding macroscopic appearance, graft histology, and clinical symptoms. Both patients recovered. In conclusion, infliximab has proven to be an effective rescue therapy in a selected group of patients with steroid and OKT3 refractory severe acute rejection after intestinal transplantation.

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.

Mycophenolate mofetil in combination with tacrolimus versus neoral after liver transplantation

MYCOPHENOLATE mofetil (MMF) is an accepted immunosuppressive agent after kidney transplantation. Possible indications for MMF after liver transplantation include: (1) rejection therapy; (2) reduction of cyclosporine or tacrolimus dosage in patients with nephro-, neuro-, or hepatotoxicity; and (3) early steroid withdrawal. The potential role of additive MMF therapy in patients with HCV cirrhosis has been explored; however, data concerning MMF induction or maintenance therapy are limited.

IL-10 increases tissue injury after selective intestinal ischemia/reperfusion.

Objective This study focused on the effect of immunoregulatory cytokines on tissue injury after intestinal ischemia/reperfusion (IR). Furthermore, the role of nitric oxide, heme oxygenase-1 (HO-1) and the transcription factor NF−&kgr;B/Rel in the disease process was evaluated. Summary Background Data Oxidative stress and inflammatory gene products contribute to ischemia/reperfusion injury (IRI). However, expression of stress proteins such as the inducible nitric oxide synthase (NOS-2) and HO-1 might also provide protection against IRI. Methods IR was achieved in Lewis rats by selective clamping of the superior mesenteric artery. IL-2 or IL-10 was administered intravenously before reperfusion. Animals were killed 1 hour, 4 hours, and 24 hours after reperfusion. Tissue destruction was assessed by hyaluronic acid (HA) and aminoaspartate-transaminase (AST) serum levels, whereas reduction of glutathione (GSH) tissue levels was used as a marker for oxidative stress. Furthermore, the activation of NF−&kgr;B/Rel and the expression of NOS-2 and HO-1 were analyzed. Results IR resulted in tissue destruction and significantly reduced GSH tissue levels in the intestines and liver. In addition, NF-&kgr;B/Rel activation and increased NOS-2 and HO-1 mRNA expression were detected in both organs after IR. IL-2 administration resulted in clinical improvement of the animals and was associated with increased NF-&kgr;B/Rel activation and enhanced NOS-2 and HO-1 mRNA expression. In contrast, IL-10 resulted in increased tissue destruction in both organs and sustained reduction of GSH levels in the intestines. Furthermore, IL-10 administration failed to enhance NF-&kgr;B/Rel activity, NOS-2 mRNA, or HO-1 mRNA expression after IR. Conclusion IL-10 resulted in increased tissue damage after intestinal IR. This detrimental effect of IL-10 might have been the result of reduced NOS-2 and HO-1 mRNA expression. In contrast, the beneficial effect of IL-2 might have relied on increased HO-1 expression and NOS-2 activity. These controversial effects of IL-2 and IL-10 might have been mediated through transcriptional regulation of NOS-2 and HO-1 gene expression.

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.

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.

Clinical use of the euglycemic hyperinsulinemic clamp for diagnosis of tacrolimus-induced insulin resistance after combined pancreas–kidney transplantation

INSULIN resistance and hyperinsulinism after pancreas transplantation are well known consequences due to immunosuppressive therapy and systemic insulin delivery. Impaired glycemic control may develop. The differentiation from pancreas rejection may be difficult; pancreas biopsy is still a diagnostic tool not widely used. Glucose tolerance tests provide information on the secretory function of the b cell. Fasting insulin levels are often variable and interpretation can be difficult. To assess insulin resistance in recipients of a pancreas–kidney transplant we employ the euglycemic hyperinsulinemic clamp (EHC) as developed by De Fronzo in 1979. The following case report illustrates the use of EHC to investigate the impact of immunosuppressant drugs in a patient with progressively deteriorating glycemic control within the first 6 months after transplantation.

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.