Nephrotoxicity represents a serious side effect of immunosuppression following liver transplantation. In order to compare the nephrotoxic action of CsA and FK506 in a clinical setting, we evaluated ...the incidence of early and late nephrotoxicity in 121 patients, 60 of whom were randomly assigned to CsA- and 61 to FK506-based immunosuppression. Early postoperative renal insufficiency (between PODs 0 and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (38.3%) and FK506 (42.6%). Early postoperative acute renal failure (ARF) (SCr > 3 mg/dl) was observed in 18.0% of patients in the FK506 treatment group and 18.3% of patients receiving CsA therapy. Approximately half the patients with ARF required hemodialysis (CsA: 11.7%; and FK506: 8.2%). All patients with early postoperative ARF requiring hemodialysis survived for more than one year. New onset of late ARF (between PODs 30 and 365) was observed in 6.6% of patients receiving FK506 therapy and in 1.7% in the CsA treatment group as a result of severe infection with multiple organ failure syndrome (MOFS). There was 100% mortality in patients with late ARF requiring hemodialysis. Etiology and prognosis of early and late ARF seem to be completely different. Early ARF was associated with severe coagulopathy and a rise in bilirubin and free hemoglobin, and was accompanied by impaired liver function. Mean onset of hemodialysis in CsA-treated patients was POD 1 and in FK506-treated patients POD 6, which disclosed a different time course of drug-specific nephrotoxicity of CsA and FK506 in early ARF. In contrast, late ARF occurred in both treatment groups only as a part of the MOFS in association with severe infections, an observation consistent with the assumption of overimmunosuppression rather than a primary nephrotoxic effect. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK506-treated patients, and represented a slowly progressing form of drug-specific nephrotoxicity of CsA and FK506. These preliminary results demonstrate a similar outcome in terms of both early and late nephrotoxicity, but longer follow-up will delineate the overall efficacy and toxicity in humans.
The authors evaluated the complication rate and outcome of side-to-side common bile duct anastomosis after human orthotopic liver transplantation.
Early 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.
Biliary 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.
One 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%.
Side-to-side common bile duct anastomosis represents a safe technique of bile duct reconstruction and leads to a low technical complication rate after human orthotopic liver transplantation. Ischemic-type biliary lesion evoked by preservation injury, arterial ischemia, cholestasis, and cholangitis may represent a new entity of biliary complication, which markedly increases the morbidity after human liver transplantation. Therefore, this complication should be the subject of further research.
Despite improvements in immunosuppression, rejection occurs in 50% of liver transplant patients and may cause significant morbidity. The most frequent cause of death after liver transplantation is ...severe infection. Determination of the cytokine network may lead to earlier detection of patients at risk for severe rejection and infection. For this purpose, 81 patients with 85 liver transplants were monitored for cytokines and neopterin on a daily basis. During the first postoperative month, 28 patients (34.6%) developed acute rejection; 14 patients were successfully treated with methylprednisolone (steroid-sensitive rejection), while 14 patients required additional treatment with FK506 and OKT3 (steroid-resistant rejection). Ten patients developed severe infections, and 11 patients experienced asymptomatic cholangitis. Patients with an uneventful postoperative course (n=37) were the control group. One-year patient survival was 88.9%: 1 patient died because of chronic rejection and Pseudomonas urosepsis; a further 4 patients died of aspergillus pneumonia and bacterial sepsis. Soluble TNF-RII, sIL-2R-, and IL-10 levels were significantly elevated 3 days prior to or at the onset of acute steroid-resistant rejection (P < or = 0.01 versus steroid-sensitive rejection and on uneventful postoperative course). An increase in IL-8, neopterin, and sTNF-RII was indicative of severe infection 3 days prior to onset of infection. In this group of patients, a simultaneous increase in IL-10 indicated a lethal outcome of severe infection. During the second week of acute steroid-resistant rejection and lethal infection, a significant rise in IL-1beta, IFN-gamma, and IL-6 was observed (P < or = 0.01 versus control groups). The different patterns in neopterin- and cytokine-increase could differentiate between severe rejection and severe infection. Furthermore, the increase in these parameters indicated severe rejection--i.e., steroid resistance at the onset of acute rejection--which could prompt us to initiate rescue therapy immediately. The ability to detect patients at risk for severe or lethal infection may result in intensified infectious screening and more aggressive antiinfectious treatment. Therefore, routine monitoring of these parameters may lead to changes in therapeutic management of severe acute rejection and infection after liver transplantation.
Neurotoxicity represents a serious complication following orthotopic liver transplantation. Neurotoxicity may be evoked by various perioperative factors or develop due to drug-specific toxicity of ...immunosuppression. We evaluated the incidence of neurotoxicity in 121 patients, 61 randomly assigned to FK506 and 60 to CsA-based immunosuppression. The incidence of moderate or severe neurotoxicity was markedly higher in patients treated with FK506 in the early postoperative period (21.3% vs. 11.7% in patients receiving CsA), after retransplantation (100% vs. 0% in patients receiving CsA), and late (8 of 10 patients; P < or = 0.05 vs. CsA). Furthermore late neurotoxicity was highly associated with severe infections and MOFS, which had a lethal outcome in more than 50% of the patients. Patients who subsequently died developed neurologic symptoms in 67% of the cases. These patients also experienced moderate or severe neurotoxicity significantly more often in the early postoperative period compared with patients with a successful outcome (50% vs. 17.3%; P < or = 0.01). However, various blood and serum parameters, including ALT, bilirubin, urea, creatinine and glucose, when analyzed alone or in multivariate fashion, also correlated significantly with the incidence and severity of early postoperative neurotoxicity, indicating that neurotoxicity following LTX may be caused by various factors and is not exclusively a drug-specific side effect of immunosuppression.
Poor initial graft function may increase postoperative morbidity including the risk of early allograft rejection. Various mediators, including immunostimulatory cytokines, may be released during ...reperfusion in relation to the extent of preservation and reperfusion injury. For this purpose, 81 patients with 85 liver transplants were monitored for cytokines, adhesion molecules, extracellular matrix (ECM) parameters, and neopterin at predefined time-points during and after transplantation. To estimate the origin of cytokine release, blood was obtained central and hepatic venously for the first 48 hr after reperfusion and subsequently from a peripheral vein. One-year patient survival was 88.9%; no relation to initial graft function was observed. Poor initial graft function failed to increase the risk for subsequent infectious complications but was associated with an increased risk of early allograft rejection. The incidence of steroid-resistant rejection was significantly increased in patients with poor initial graft function (35.7% versus 12.7% in patients with good and moderate initial graft function; P < or = 0.05). Various cytokines, adhesion molecules, and ECM parameters including sTNF-RII, sIL-2R, IL-8, IL-10, sVCAM-1, E-selectin, hyaluronic acid, sialic acid, and laminin correlated significantly with the extent of preservation and reperfusion injury. Although none of these parameters was more appropriate in determining the extent of preservation and reperfusion injury than currently established parameters (AST, ALT, and color and amount of bile production), the combined increase in these parameters may not only promote tissue repair but may also perpetuate liver allograft injury and thereby cause significant morbidity. Besides cytokines and adhesion molecules, the ECM may play a pivotal role in determining repair or ongoing tissue injury. Ongoing changes at the microvasculature and basement membrane may result in an increase of local and circulating cytokines and adhesion molecules, which increase the risk of subsequent early allograft rejection. Furthermore, the increase in sTNF-RII, E-selectin, and laminin during reperfusion was predictive of subsequent development of acute allograft rejection. These observations may be of value for further strategies to decrease reperfusion injury and prevent early allograft rejection.
IL-2 Antagonists: The European Perspective Platz, K.-P.; Braun, F.; Fändrich, F. ...
Transplantation proceedings,
05/2005, Letnik:
37, Številka:
4
Journal Article, Conference Proceeding
Recenzirano
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.
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.
FK506 has been proven effective for prevention and treatment of liver allograft rejection. Herein, we compare FK506-based immunosuppression with an effective quadruple immunosuppressive regimen, ...including cyclosporine and antithymocyte globulin. The results of a single center participating in the European multicenter FK506 study are reported, including immunosuppressive efficacy as well as toxicity. One-year patient and graft survival was 96.7% and 90.0% for the CsA group and 90.2% and 88.5% for the FK506 group, which is not statistically different. The incidence and severity of acute rejection episodes during the first postoperative year was similar in both treatment groups with 34.4% and 33.3% for the FK506 and CsA treatment group, respectively. Immunosuppressive potency was better for the FK506 group compared with the CsA group according to the incidence of chronic rejection. Furthermore, 5 patients (8.3%) required conversion to FK506 for immunological reasons, i.e., refractory acute or chronic rejection. The incidence of moderate and severe neurotoxicity during the early postoperative period was higher in the FK506 group (21.3%) compared with the CsA group (11.7%), while the incidence of renal insufficiency and acute renal failure was similar (18.0% and 18.3% for the FK506 and CsA treatment groups, respectively). The incidence of CMV infection was significantly higher under treatment with CsA (25.0%) than with FK506 (6.6%) (P < or = 0.05), while the incidence of pneumonia (13.1% and 13.3%), cholangitis (29.5% and 26.7%), and urinary tract infection (39.3% and 28.3% for the FK506 and CsA treatment groups, respectively) was similar in both treatment groups. However, infection was more serious in some cases treated with FK506, and evolved as the main cause of death in the FK506 treatment group. Therefore, caution should be paid to over immunosuppression and toxicity in FK506-treated patients. Regarding the monitoring of FK506, FK506 plasma level failed to be a reliable indicator, and therefore we recommend measurement of whole blood FK506 levels. Our data indicate that immunosuppressive potency of FK506 is greater than that of CsA, especially concerning the incidence of chronic rejection.
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.
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