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Biomedical subjects

A R Mueller

Publications and source records attributed to A R Mueller.

At least 55 records · Page 3Linked to original sources
PubMed1996

Cytokine pattern during rejection and infection after liver transplantation--improvements in postoperative monitoring?

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.

Alanine Transaminase↗
PubMed1996

The release of cytokines, adhesion molecules, and extracellular matrix parameters during and after reperfusion in human liver transplantation.

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.

Adult↗
PubMed1996

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.

Biopterins↗
PubMed1996

Hepatitis C: indication for anti-viral therapy?

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 histologically 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 < or = 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 necessity for a specific anti-viral therapy.

Graft Rejection↗
PubMed1996

Management of acute steroid-resistant rejection after liver transplantation.

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.

Acute Disease↗
PubMed1996

Liver failure in erythropoietic protoporphyria associated with choledocholithiasis and severe post-transplantation polyneuropathy.

In a 58-year-old woman with erythropoietic protoporphyria, asymptomatic liver involvement had been diagnosed 12 years earlier. For more than 20 years the patient had been known to have symptomatic gallstones. A mild polyneuropathy of the lower limbs had been diagnosed several years ago. In December 1992, she presented with colicky upper abdominal pain, dyspepsia and mild jaundice. Diagnosis of beginning cholestasis in erythrohepatic protoporphyria and coincidental choledocholithiasis was made. A causal relation between choledocholithiasis and deterioration of liver function was assumed. Endoscopic extraction of the bile duct stones, however, could not prevent the development of terminal hepatic failure. Biochemically, an excessive protoporphyrinemia and coproporphyrinuria were found. Five weeks after presentation, the patient underwent orthotopic liver transplantation. Immediately after the operation she developed a severe axonal neuropathy with cranial nerve involvement. One year after transplantation, her general condition has markedly improved, but there is still a disabling polyneuropathy. Recently, there were single reports on patients with very similar neurological symptoms following liver transplantation in erythropoietic protoporphyria. This case supports the assumption of a distinct protoporphyrin-induced neural damage in severe hepatic failure.

Alanine Transaminase↗
PubMed1995

Comparison of FK506- and cyclosporine-based immunosuppression in primary orthotopic liver transplantation. A single center experience.

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.

Adolescent↗
PubMed1995

Toxicity versus rejection--or why conversions between cyclosporine A and FK506 were performed after liver transplantation.

The introduction of cyclosporine A (CsA) and FK506 significantly improved the outcome of liver transplantation. However, the postoperative course and outcome of liver transplant recipients in still compromised by rejection, over-immunosuppression-induced infection and immunosuppression-associated toxicity. In the present study, we evaluated the reason for conversion between immunosuppressive regimens in 121 patients, 60 treated with FK506 and 61 patients treated with CsA-based immunosuppression. Five patients treated primarily with CsA (8.3%) were converted to FK506 therapy because of refractory acute of chronic rejection within 12 months following liver transplantation (LTX). In 2 patients, conversion was performed after Re-LTX. In 4 of these 5 patients, rejection was successfully treated according to histological and laboratory investigations, while in the remaining patient, graft function improved with persisting histological evidence of chronic rejection. Moderate and severe neurologic symptoms during the early postoperative period, i.e. organic brain syndromes (OBS), seizures, hemiparesis, dysphasia, dysathria and cerebellar symptoms were observed in 21.3% of patients treated with FK506 and in 11.7% of patients treated with CsA (p = n.s.). Five patients treated primarily with FK506 were converted to CsA due to severe neurotoxicity. Early postoperative renal insufficiency was observed to a similar extent with 42.6% of FK506- and 36.7% of CsA-treated patients. 8.3% of FK506-treated patients and 11.7% of CsA-treated patients required hemodialysis (p = n.s.) There patients were converted from FK506 to CsA due to persisting renal insufficiency. Moderate and severe neurologic symptoms were observed more frequently under treatment with FK506 than CsA, and all conversions from FK506 to CsA (13.3%) were performed because of neuro- or nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine↗
PubMed1995

The optimal immunosuppressant after liver transplantation according to diagnosis: cyclosporine A or FK506?

Since we may soon be able to choose between primarily CsA- or FK506-based immunosuppression, it is important to establish the superior immunosuppressive agent for the individual patient. In the present study, 121 patients, 61 randomly assigned to FK506- and 60 assigned to CsA-based immunosuppression, were analyzed according to the primary diagnosis for liver transplantation. One-year patient survival was similar in all groups. However, the incidence and severity of acute rejection within the 1st year after transplantation was significantly higher in patients transplanted due to HCV disease who were receiving FK506 (58.8%) compared with those patients receiving CsA (27.8%; p < or = 0.05). Furthermore, the incidence of moderate and severe neurotoxicity was significantly higher during the 1st month after LTX in patients transplanted owing to HCV disease treated with FK506 (35.3%) compared with those patients receiving CsA (16.7%; p < or = 0.05). Irrespective of the immunosuppressive regimen, the incidence of early postoperative neurotoxicity was significantly lower in patients transplanted owing to HBV disease, alcoholic cirrhosis and various other liver diseases summarized than in patients transplanted due to HCV disease receiving FK506 therapy. During the 1st year, the incidence and severity of rejection in patients transplanted due to alcoholic cirrhosis and PBC was significantly lower in patients treated with FK506 (11.1% for both groups) compared with those patients receiving CsA (54.5% and 60.0%, respectively; p < or = 0.05. Furthermore, this was accompanied by a lower incidence of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗