Peter Neuhaus - Academia.edu (original) (raw)

Papers by Peter Neuhaus

Transplantation, 2002

Today, the major problem in organ transplantation is not acute graft rejection but chronic graft ... more Today, the major problem in organ transplantation is not acute graft rejection but chronic graft deterioration. In addition to alloantigen-specific events, alloantigen independent factors like donor age, previous diseases, consequences of brain death, and perioperative events of ischemia/reperfusion injury have a major impact on long-term graft function. The induction of the stress protein heme oxygenase-1 (HO-1) protects cells from injury and apoptosis. Here, we tested the protective effects of HO-1 induction in a clinically relevant kidney transplant model. Induction of HO-1 expression following cobalt-protoporphyrin (CoPP) treatment in organ donors prolonged graft survival and long-term function remarkably following extended periods of ischemia. Positive effects were observed with both optimal and marginal grafts from old donor animals. Structural changes characteristic for chronic rejection, as well as graft infiltration by monocytes/macrophages and CD8؉ T cells, were substantially reduced following HO-1 induction. Up-regulation of HO-1 expression before organ transplantation was also associated with reduced levels for tumor necrosis factor (TNF)-␣ mRNA, increased levels for interferon (IFN)-␥, and bcl-x, and insignificant differences for CD25, interleukin (IL)-2, IL-4, IL-6, and IL-10 mRNA levels. The significant improvement of longterm graft function following induction of HO-1 ex-pression in donor organs suggests that this strategy may be a novel clinical treatment option with particular relevance for transplantation of marginal organs.

Lancet, 2000

Interpretation The normalised intrinsic mortality risk can be combined with the relative risk rat... more Interpretation The normalised intrinsic mortality risk can be combined with the relative risk ratios of known risk factors to better estimate the mortality risk of a given procedure in a given patient. Centres can assess performance by removing potential bias of donor and recipient selection.

Liver Transplantation, 2003

The European Liver Transplant Registry (ELTR) currently allows for the analysis of 44,286 liver t... more The European Liver Transplant Registry (ELTR) currently allows for the analysis of 44,286 liver transplantations (LTs) performed on 39,196 patients in a 13-year period. After an exponential increase, the number of LTs is plateauing due to a lack of organs. To cope with this, alternatives to cadaveric LT, such as split LT, domino LT, or living-related LT (LRLT) are being used increasingly. They now account for 11% of all procedures. One of the most important findings in the evolution of LT is the considerable improvement of results along time with, for the mean time, a one-year survival of 83%, all indications confounded. The improvement is particularly significant for cancers. This improvement is mainly represented by hepatocellular carcinoma, with a gain of 17% for 5-year survival rate from 1990 to 2000. Increasingly, older donors are used to augment the donor pool and older recipients are transplanted due to improved results and a better selection of patients. More than two thirds of deaths and three quarters of retransplantations occurred within the first year of transplantation. Retransplantation is associated with much less optimal results than first LT. One of the prominent features of recent years is the development of LRLT. LRLT is now performed by almost half of the European centers. As with split LT or domino LT, LRLT aims to provide more patients to be transplanted. Special attention is paid to reducing the risk for the donor, which is now estimated to be 0.5% mortality and 21% postoperative morbidity. (Liver Transpl 2003;9: 1231-1243

Liver Transplantation, 2001

Acute hepatic allograft rejection occurs in approximately 50% to 60% of the patients undergoing l... more Acute hepatic allograft rejection occurs in approximately 50% to 60% of the patients undergoing liver transplantation. In this study, we compared the rate of acute rejection in liver transplant recipients randomized in a doubleblind comparative study to treatment with mycophenolate mofetil (MMF) or azathioprine (AZA), both in combination with cyclosporine and corticosteroids. Five hundred sixty-five primary liver transplant recipients were randomly assigned to treatment with MMF, 1 g twice daily intravenously followed by 1.5 g twice daily orally (n ‫؍‬ 278), or AZA, 1.0 to 2.0 mg/kg/d intravenously followed by oral administration (n ‫؍‬ 287), in combination with cyclosporine and corticosteroids. Patients were followed up for at least 1 year, and efficacy analysis was based on intent-to-treat methods. Acute rejection was defined according to the Banff histological criteria. The two study groups were balanced for demographic and clinical baseline characteristics. The incidence of acute rejection or graft loss was 47.7% in the AZA patients and 38.5% in the MMF patients (P < .03). The incidence of biopsyproven and treated rejection censoring for graft loss was 40.0% in the AZA group versus 31.0% in the MMF group (P < .06). Steroid-resistant rejection requiring treatment with either OKT3 or antithymocyte globulin occurred in 8.2% of AZA patients versus 3.8% in MMF patients (P < .02). Patient and graft survival rates at 1 year posttransplantation were 85.4% in the AZA group and 85.3% in the MMF group (P ‫؍‬ not significant). MMF was superior to AZA in preventing acute rejection in the first 6 months posttransplantation. MMF and AZA were equivalent in preventing graft loss at 1 year, and the safety profiles between the two immunosuppressive agents were similar. (Liver Transpl 2001;7:442-450.)

Hepatology, 2003

Michel Eichelbaum,' Many drugs that are substrates of CYP3A4, the major human drug-metabolizing c... more Michel Eichelbaum,' Many drugs that are substrates of CYP3A4, the major human drug-metabolizing cytochrome P450 (CYP), show higher clearance in women than in men. Although this effect is believed to be related to drug metabolism, the underlying cause has not been elucidated. We investigated CYP3A4 in a large collection (n = 94) of well-characterized surgical liver samples and found 2-fold higher CYP3A4 levels in female compared with male samples (P < ,0001) and a corresponding 50% increase in the CYP3A-dependent N-dealkylation of verapamil (P < .O1). This expression difference was not due to preferential induction in women following higher drug exposure because it was even larger in a subgroup not previously exposed to drugs. Higher expression in women was also found for CYP3A4 messenger RNA (mRNA) transcripts, suggesting a pretranslational mechanism. Expression of the pregnane X receptor (PXR), which is crucially involved in CYP3A4 induction by xenobiotics, was strongly correlated to CYP3A4 at the mRNA level in all individuals as well as in the subgroup not exposed to drugs (r = 0.81; P < .OOOl), but no sex-dependent expression of PXR mRNA was found. The ABC transporter P-glycoprotein, which has been proposed to be implicated in the mechanism of sex-dependent drug clearance, was also not differentially expressed. The influence of drug treatment on expression was examined from patient drug histories, and strong induction of CYP3A4 by carbamazepine and St. John's wort was found. In conclusion, sex, in addition to PXR and drug exposure, is a major factor for CYP3A4 expression in humans, thus explaining many of the previous observations of sex-dependent drug clearance. (HEPATOLOGY 2003;38:978-988.) YP3A4 is the most abundantly expressed member of the cytochrome P450 (CYP) superfamily C in human liver and intestine, where it contributes critically to the first-pass metabolism of about one half of all drugs Wide interindividual and intraindividual variability in expression and function of CYP3A4 is considered a major reason for unpredictable drug responses and drug toxicity but seems to be largely independent of genetic p0lymorphism.3,~ The reasons for Abbreviations: C P , cytochrome P450; PXR, pregnane X receptor; CAR, constitutive androstane receptor; MDR, multidrug resistance; mRNA, messenger M A . From the 'Dr. Margarete Fisrher-Bosrh Institute of Clinical Pharmacology, Stuttgart; and 2Department of S u r p y , Charite, Campus Virchow-Clinic, Hum-

The human cytochrome P450, CYP2B6, is involved in the metabolism of several therapeutically impor... more The human cytochrome P450, CYP2B6, is involved in the metabolism of several therapeutically important drugs and environmental or abused toxicants. In this study, we present the ®rst systematic investigation of genetic polymorphism in the CYP2B6 gene on chromosome 19. A speci®c direct sequencing strategy was developed based on CYP2B6 and CYP2B7 genomic sequence information and DNA from 35 subjects was completely analysed for mutations throughout all nine exons and their exon±intron boundaries. A total of nine novel point mutations were identi®ed, of which ®ve result in amino acid substitutions in exon 1 (C64T, Arg 22 Cys), exon 4 (G516T, Gln 172 His), exon 5 (C777A, Ser 259 Arg and A785G, Lys 262 Arg) and exon 9 (C1459T, Arg 487 Cys) and four are silent mutations (C78T, G216C, G714A and C732T). Polymerase chain reaction-restriction fragment length polymorphism tests were developed to detect each of the ®ve nonsynonymous mutations in genomic DNA. By screening a population of 215 subjects the C64T, G516T, C777A, A785G and C1459T mutations were found at frequencies of 5.3%, 28.6%, 0.5%, 32.6% and 14.0%, respectively. Haplotype analysis revealed six different mutant alleles termed CYP2B6 Ã 2 (C64T), Ã 3 (C777A), Ã 4 (A785G), Ã 5 (C1459T), Ã 6 (G516T and A785G) and Ã 7 (G516T, A785G and C1459T). By analysing a large number of human liver samples, signi®cantly reduced CYP2B6 protein expression and S-mephenytoin N-demethylase activity were found in carriers of the C1459T (R487C) mutation (alleles Ã 5 and Ã 7). These data demonstrate that the extensive interindividual variability of CYP2B6 expression and function is not only due to regulatory phenomena, but also caused by a common genetic polymorphism.

Transplant International, 2000

Abstract From September 1988 through April 1998, 1000 liver transplantations were performed on 91... more Abstract From September 1988 through April 1998, 1000 liver transplantations were performed on 911 patients. During the postoperative control examinations of 837 patients, we found 23 (2.74%) with hepatic artery thromboses, 27 stenoses of the hepatic artery (3.22%), and 6 aneurysms of the graft artery. Seventeen patients underwent retransplantation because of arterial complications. Depending on the clinical symptoms, we treated both the local situation as well as the resulting complications of inadequate arterial graft flow. The aneurysms were primarily treated surgically. The first choice of treatment of stenoses was balloon angioplasty. Early postoperative artery thromboses were also treated surgically by thrombectomy in selected cases. For the resulting biliary and local septic complications we preferred endoscopic and drainage procedures. Our clinical experiences have led us to find pretransplantation angiography recommendable, especially in the case of splanchnic artery stenoses, for bypassing from the aorta for arterial perfusion of the graft.

Hepatology, 1998

“Escape” variants of hepatitis B virus (HBV) can cause infection despite previous immunization. T... more “Escape” variants of hepatitis B virus (HBV) can cause infection despite previous immunization. These viruses show alterations of the immunogenic major hydrophilic loop of the HBV small surface protein (s-protein). We studied whether HBV “escape” variants were selected in patients with graft infection after liver transplantation for HBV-related diseases who received passive immunoprophylaxis with high-dose polyclonal hepatitis B hyperimmune globulin (HBIG). For that, pre- and posttransplantation sera of 34 patients were analyzed for the occurence of HBV S-gene variants. In addition, binding of in vitro–translated variant s-proteins to HBIG was studied. Variants with exchanges of amino acid (aa) 144 (s144) in HBV genotype A and 145 in genotype D (s145) were found to emerge, persist, and predominate during HBIG, and thus fulfilled criteria of “escape” variants selected. In addition to already-known variants sG145R/K/E, we could demonstrate that newly described variants sX144G and sG145A were antigenically altered and showed impaired recognition by polyclonal HBIG in vitro. Diminished recognition of variant s-proteins correlated with the failure of HBIG to prevent infection of the liver graft with antigenically altered variant HBV. Patients infected with “escape” variants s144 or s145 showed a worse clinical outcome compared with the other patients on high-dose, long-term HBIG prophylaxis (44% vs. 23% graft failure caused by HBV infection). Our results suggest that antigenically altered HBV variants s144 and s145 can be selected by HBIG and can influence clinical outcome after liver transplantation.

Transplantation, 2002

Early enteral nutrition with solutions containing prebiotics (fiber) and probiotics (Lactobacillu... more Early enteral nutrition with solutions containing prebiotics (fiber) and probiotics (Lactobacillus) is suggested to reduce bacterial translocation and minimize the incidence of infections after liver transplantation. In a prospective, randomized placebo-controlled trial consisting of 95 patients, we compared the incidence of postoperative infections and other complications after liver transplantation among three different groups, all supplied with early enteral nutrition: (a) standard formula plus selective bowel decontamination (SBD), (b) fiber-containing formula plus living Lactobacillus plantarum 299, and (c) fiber-containing formula plus heat-killed L plantarum 299. The groups were comparable regarding preoperative American Society of Anesthesiologists classification, Child-Pugh classification of cirrhosis, operative data, and degree of immunosuppression. The patients who received living lactobacilli plus fiber developed significantly fewer bacterial infections (13%) than the patients with SBD (48%). The incidence of infections was 34% in the group with inactivated lactobacilli and fiber. Cholangitis and pneumonia were the leading infections and enterococci the most commonly isolated bacteria. In the living Lactobacillus group, the mean duration of antibiotic therapy, the mean total hospital stay, and the stay on the intensive care unit were also shorter than in the groups with inactivated lactobacilli and fiber as well as with SBD. However, these differences did not reach statistical significance. Early enteral nutrition with fiber-containing solutions and living L plantarum 299 was well tolerated. It decreases markedly the rate of postoperative infections both in comparison with inactivated L plantarum 299 and significantly with SBD and a standard enteral nutrition formula. As it is a cheap and feasible alternative to SBD, further studies should evaluate whether this ecoimmunonutrition should be already started while patients are on the waiting list for transplantation.

Liver Transplantation, 2003

The incidence, clinical presentation, therapeutic options, and outcome of hepatic artery thrombos... more The incidence, clinical presentation, therapeutic options, and outcome of hepatic artery thrombosis (HAT) were analyzed in a series of 1,192 consecutive adult orthotopic liver transplantations (OLTs). HAT after OLT was observed in 30 cases, resulting in an incidence of 2.5%. The incidence of HAT increased 5.76-fold when the donor hepatic artery was reconstructed with an interposition graft to the supraceliac aorta (P < .05). Early HAT (within the first 30 days after OLT) occurred in 14 of these patients (46.7%), whereas in 16 patients (53.3%), HAT occurred beyond 30 days post-OLT. Clinical presentation of HAT ranged from an increase in serum transaminase levels with or without cholestasis to liver abscess and biliary complications, including cholangitis, bile duct stenosis or necrosis, to liver dysfunction and failure. Impairment of graft function was observed in patients with early HAT, whereas biliary tract destruction was seen more often in patients with late HAT. In only 1 patient was HAT clinically asymptomatic. Therapy consisted of recombinant plasminogen lysis with hepaticojejunostomy, liver abscess drainage, endoscopy or surveillance, and surgical thrombectomy. In 14 of 30 patients (46.7%), the occurrence of HAT required re-OLT. Nine patients with HAT died during follow-up; however, only 4 of these deaths were related to HAT, resulting in a mortality rate of 13.3%. Our results indicate that HAT is a rare but serious complication after OLT, requiring re-OLT in almost 50% of patients. In particular, conservative treatment modalities may significantly prolong graft survival, thus postponing re-OLT. (Liver Transpl 2003;9:612-620.)

Hepatology, 2001

Selection of patients suffering from hepatocellular carcinoma (HCC) in cirrhosis for liver transp... more Selection of patients suffering from hepatocellular carcinoma (HCC) in cirrhosis for liver transplantation follows limits of number and diameter of tumor nodules. It has not been investigated whether there is a correlation of these parameters with vascular invasion. From 1989 to 2000, 1,188 liver transplantations were performed in 1,087 patients, including 120 patients (11%) with an HCC in cirrhosis. Selection criteria were a maximal diameter of up to 5 cm if the tumor appeared to be uninodular or of up to 3 cm in the case of 2 or 3 nodules. The postoperative mortality rate was 1.7%. One-, 5-, and 10-year survival was 90%, 71%, and 60%, respectively. In 940 transplantation patients without an HCC, these rates were 93%, 87%, and 83% (P < .0001). Vascular invasion and histopathologic grading were identified as prognostic parameters by multivariate analysis. In a logistic regression analysis, histopathologic grading and maximal diameter showed a significant correlation with a vascular invasion. Analyzing tumors larger than 5 cm, i.e., tumors not fulfilling the selection criteria as a result of diagnostic inaccuracy or progression thereafter, the rates of vascular invasion were significantly (P < .01) lower in patients suffering from well-differentiated tumors (25%) when compared with moderately and poorly differentiated tumors (100%). Liver transplantation is a safe and effective longterm treatment for small HCC in cirrhosis. Tumor diameter and number of nodules in correlation with the histopathologic grading were predictive of a vascular invasion only in HCC larger than 5 cm. (HEPATOLOGY 2001;33:1080-1086.)

Journal of Hepatology, 2004

Journal of Clinical Investigation, 1992

The present study was designed to determine whether *N 0 produced in vivo during the rejection of... more The present study was designed to determine whether *N 0 produced in vivo during the rejection of histoincompatible tissues might permit serum NOQ/N0 levels to serve as markers of a rejection reaction. Rat syngeneic and allogeneic liver, heart, bone marrow/spleen cell, small bowel, skin, and sponge matrix grafts were performed and the stable endproducts of N 0, NOQ/N0, were serially assayed in the serum of the grafted animals. A significant rise of serum NOQ/NOlevels in the allografted animals preceded the onset of clinical signs of rejection or graft-versus-host disease, with the exception of the skin and sponge matrix graft models, where elevated serum NO /NO-levels were never observed. In all transplant models, normal serum NO /NO-levels were observed at all times in animals that received syngeneic grafts. Furthermore, treatment ofallograft recipients with the immunosuppressive agents FK 506 or cyclosporine A inhibited N 0 production. Determination of serum creatinine levels demonstrated that the elevated serum NO /NO-levels were not caused by kidney dysfunction. Serum NOQ/NOlevels might be useful early serum markers of the initiation of a rejection reaction or graft-versushost disease when functional markers of graft dysfunction are not apparent. (J. Clin. Invest. 1992. 90:679-683.)

Annals of Surgery, 1994

The authors evaluated the complication rate and outcome of side-to-side common bile duct anastomo... more The authors evaluated the complication rate and outcome of side-to-side common bile duct anastomosis after human orthotopic liver transplantation.

Clinical Transplantation, 2000

Complications involving the portal vein or the vena cava, are rare after orthotopic liver transpl... more Complications involving the portal vein or the vena cava, are rare after orthotopic liver transplantation. We report on the incidence and treatment of venous complications following 1000 orthotopic liver transplantations in 911 patients. Twenty-six of the adult patients (2.7%) suffered from portal complications after transplantation, whereas complications of the vena cava were observed in only 17 patients (1.8%). Technical problems or recurrence of the underlying disease (e.g. Budd-Chiari syndrome) accounted for the majority of complications of the vena cava, whereas alteration of the vessel wall or splenectomy during transplantation could be identified as important risk factors for portal vein complications. In patients undergoing modification of the standard end-to-end veno-venous anastomosis of the portal vein due to pathological changes of the vessel wall, complications occurred in 8.3%, whereas only 2.4% of patients who received a standard anastomosis of the portal vein experienced complications of the portal vein. Furthermore, splenectomy during transplantation was also associated with an increased incidence of portal vein complications (10.5 vs. 2.2% in patients without splenectomy). Treatment was dependent on the signs and symptoms of the patients, and varied considerably between patients with portal vein complications and patients suffering from complications of the vena cava. Complications of the vena cava led to retransplantation in about one-third of the patients, whereas in patients with occlusion of the portal vein, retransplantation was necessary in only 15%, and more than half of the patients suffering from portal vein complications did not require any treatment at all. Usually, treatment of patients with portal vein complications only became necessary when additional complications such as arterial occlusion or bile duct injuries occurred.

Transplantation, 2004

Recurrence of hepatitis C (HCV) infection after orthotopic liver transplantation (OLT) in HCV-pos... more Recurrence of hepatitis C (HCV) infection after orthotopic liver transplantation (OLT) in HCV-positive patients is almost universal. Severity of graft hepatitis increases during the long-term follow-up, and up to 30% of patients develop severe graft hepatitis and cirrhosis. However, there are still no clear predictors for severe recurrence. The aim of this study was to examine the 10-year outcome and risk factors for graft failure caused by HCV recurrence. In a prospective analysis, 234 OLTs in 209 HCV-positive patients with a median age of 53 years were analyzed. Immunosuppression was based on cyclosporine A or tacrolimus in different protocols. Predictors for outcome were genotype, viremia, donor variables, recipient demographics, postoperative immunosuppression, and human leukocyte antigen (HLA) compatibilities. Actuarial 5-, and 10-year patient survival was 75.8% and 68.8%. Eighteen of 209 (8.7%) patients died because of HCV recurrence, which was responsible for 35.9% of the total 53 deaths. Significant risk factors for HCV-related graft failure in an univariate analysis were multiple steroid pulses, use of OKT3, and donor age greater than 40. However, in a multivariate analysis, multiple rejection treatments with steroids and OKT3 treatment proved to be significantly associated with HCV-related graft loss. The analysis of causes leading to graft failure in patients with HCV showed that HCV recurrence is responsible for one of three deaths in HCV-positive patients. Rejection treatment contributed significantly to an enhanced risk for HCV-related graft loss. New antiviral treatments, as well as adapted immunosuppressive protocols, will be necessary to further improve the outcome of HCV-positive patients after liver transplantation.

Transplantation, 1993

Treatment with monoclonal IL-2 receptor antibodies has been successfully used for immunosuppressi... more Treatment with monoclonal IL-2 receptor antibodies has been successfully used for immunosuppressive induction therapy following organ transplantation in the recent past. The present study was conducted to compare for the first time a cyclosporine-based quadruple immunosuppressive regimen including a monoclonal IL-2 receptor antibody or ATG as induction therapy after orthotopic liver transplantation. In two groups of 33 patients each, postoperative survival, graft biopsies, liver function enzymes, and the clinical courses after OLT were evaluated. Our results indicate that monoclonal IL-2 receptor antibody therapy as part of a quadruple immunosuppressive regimen is better tolerated and is at least as effective as ATG in prevention of allograft rejection following OLT. Furthermore, our data indicate that a slightly better liver function in general and a lower incidence of rejection reactions necessitating treatment could be observed in the group of patients treated with the monoclonal IL-2 receptor antibody. This study provides evidence that monoclonal IL-2 receptor antibody therapy may be a useful tool for the immunosuppressive induction therapy following clinical orthotopic liver transplantation.

Transplantation, 2002

Lancet, 2000

Liver Transplantation, 2003

Liver Transplantation, 2001

Hepatology, 2003

Transplant International, 2000

Hepatology, 1998

Transplantation, 2002

Liver Transplantation, 2003

Hepatology, 2001

Journal of Hepatology, 2004

Journal of Clinical Investigation, 1992

Annals of Surgery, 1994

Clinical Transplantation, 2000

Transplantation, 2004

Transplantation, 1993