Renal impairment after liver transplantation - a pilot trial of calcineurin inhibitor-free vs. calcineurin inhibitor sparing immunosuppression in patients with mildly impaired renal function after liver transplantation.

OBJECTIVES: Chronic kidney disease is frequent in patients after orthotopic liver transplantation (OLT) and has impact on survival. Patients receiving calcineurin inhibitors (CNI) are at increased risk to develop impaired renal function. Early CNI reduction and concomitant use of mycophenolat mofetil (MMF) has been shown to improve renal function. METHODS: The aim of this trial was to compare dose-reduced CNI/MMF versus CNI-free MMF/prednisone-based treatment in stable patients after OLT with respect to glomerular filtration rate (GFR). 21 patients (GFR 44.9 ' 9.9 mL/min/1.73m2 measured by 99m-Tc-DTPA-clearance, serum creatinine (SCr) 1.5 ' 0.42 mg/dL) were randomized either to exchange CNI for 10 mg prednisone (group 1; n = 8) or to receive CNI at 25% of the initial dose (group 2; n = 13) each in combination with 1000 mg MMF b.i.d. RESULTS: At month 12 mean SCr (-0.3 ' 0.4 mg/dL, p = 0.031) and GFR improved (8.6 ' 13.1 mL/min/ 1.73m superset2, p = 0.015) in group 2 but remained unchanged in group 1. Main side effects were gastroinstestinal symptoms (14.3%) and infections (4.8%). Two biopsy proven, steroid-responsive rejections occurred. In group 1 mean diastolic blood pressure (BP) increased by 11 ' 22 mmHg (p = 0.03). CONCLUSIONS: Reduced dose CNI in combination with MMF but not CNI-free-immunosuppression leads to improvement of GFR in patients with moderately elevated SCr levels after OLT. Addition of steroids resulted in increased diastolic blood pressure presumably counterbalancing the benefits of CNI withdrawal on renal function.

Anti-neutrophil antibodies in primary sclerosing cholangitis.

Anti-neutrophil specific antibodies are detected in up to 88% of patients with PSC. The labelling pattern of neutrophils produced by these antibodies when examined by indirect immunofluorescence microscopy is distinct from that produced by anti-neutrophil cytoplasmic antibodies (ANCA) in vasculitic diseases. The antigen(s) recognized by anti-neutrophil antibodies in PSC is not yet known but appears to be localized to the periphery of the nucleus. Accordingly, the term peripheral anti-neutrophil nuclear antibodies (p-ANNA) is more appropriate than the frequently used p-ANCA. As the titre of p-ANNA in PSC does not correlate with disease-specific clinical parameters, they are not useful markers for the management of patients. However, the high prevalence of p-ANNA in PSC makes them a reasonable diagnostic marker if used in conjunction with other standard diagnostic tests. The role of anti-neutrophil antibodies in the pathogenesis of PSC, if any, remains to be established.

[Stent implantation as a palliative therapeutic measure in tumor-induced stenoses of the large veins of the body]. / Stentimplantation als palliative Therapiemassnahme bei tumorinduzierten Stenosen der grossen Körpervenen.

PURPOSE: Self-expandable metallic stents were used to treat patients with malignant venous obstructions to determine their effectiveness in producing symptomatic palliation. METHODS: 20 patients with a total of 28 tumour-induced obstructions of the superior vena cava (n = 13), the inferior vena cava (n = 4), the subclavian (n = 4), the innominate (n = 5) and the iliac veins (n = 2) were treated with self-expandable metallic stents. 38 Gianturco stents and 21 Wallstents were applied. Patients were heparinised during the procedure and up to three days afterwards. RESULTS: In all patients correct positioning of the stents was achieved. In 16 patients stent placement resulted in relief of their symptoms. In 8 patients the symptoms completely disappeared without recurrence until death as a result of tumour progression. The follow-up ranged from 10 days to 14 months. In 8 still living patients no re-obstruction occurred (follow-up average three months). In one patient thrombotic stent occlusion occurred 6 days after the procedure; the v. cava superior was reopened again by local urokinase therapy. Three patients finally developed re-occlusion due to tumour progression. In one patient stent placement was complicated by migration of the Gianturco stent one day after stent implantation and reocclusion of the subclavian vein. CONCLUSION: The application of self-expandable metallic stents in patients with malignant venous obstruction is a useful palliative therapy.

Diagnostic accuracy of atypical p-ANCA in autoimmune hepatitis using ROC- and multivariate regression analysis.

INTRODUCTION: Antineutrophil cytoplasmic antibodies (atypical p-ANCA) are detected at high prevalence in sera from patients with autoimmune hepatitis (AIH), but their diagnostic relevance for AIH has not been systematically evaluated so far. METHODS: Here, we studied sera from 357 patients with autoimmune (autoimmune hepatitis n=175, primary sclerosing cholangitis (PSC) n=35, primary biliary cirrhosis n=45), non-autoimmune chronic liver disease (alcoholic liver cirrhosis n=62; chronic hepatitis C virus infection (HCV) n=21) or healthy controls (n=19) for the presence of various non-organ specific autoantibodies. Atypical p-ANCA, antinuclear antibodies (ANA), antibodies against smooth muscles (SMA), antibodies against liver/kidney microsomes (anti-Lkm1) and antimitochondrial antibodies (AMA) were detected by indirect immunofluorescence microscopy, antibodies against the M2 antigen (anti-M2), antibodies against soluble liver antigen (anti-SLA/LP) and anti-Lkm1 by using enzyme linked immunosorbent assays. To define the diagnostic precision of the autoantibodies, results of autoantibody testing were analyzed by receiver operating characteristics (ROC) and forward conditional logistic regression analysis. RESULTS: Atypical p-ANCA were detected at high prevalence in sera from patients with AIH (81%) and PSC (94%). ROC- and logistic regression analysis revealed atypical p-ANCA and SMA, but not ANA as significant diagnostic seromarkers for AIH (atypical p-ANCA: AUC 0.754+/-0.026, odds ratio [OR] 3.4; SMA: 0.652+/-0.028, OR 4.1). Atypical p-ANCA also emerged as the only diagnostically relevant seromarker for PSC (AUC 0.690+/-0.04, OR 3.4). None of the tested antibodies yielded a significant diagnostic accuracy for patients with alcoholic liver cirrhosis, HCV or healthy controls. CONCLUSIONS: Atypical p-ANCA along with SMA represent a seromarker with high diagnostic accuracy for AIH and should be explicitly considered in a revised version of the diagnostic score for AIH.

Change in the fatty acid pattern of erythrocyte membrane phospholipids after oral supplementation of specific fatty acids in patients with gastrointestinal diseases.

BACKGROUND/OBJECTIVES: The fatty acid pattern of membrane phospholipids is suggested to affect membrane fluidity and epithelial barrier function as a result of membrane fatty acid unsaturation. The incorporation of n-3 polyunsaturated fatty acids (PUFAs) into membrane phospholipids may diminish inflammatory potential in patients with gastrointestinal diseases. The aim of this study was to improve the fatty acid profile of erythrocyte membrane phospholipids after oral supplementation of specific fatty acids in patients with maldigestion and/or malabsorption. SUBJECTS/METHODS: We conducted a randomized, double-blind, controlled trial. A total of 48 patients with gastrointestinal diseases received either fat-soluble vitamins A,D,E,K (ADEK) or ADEK plus fatty acids alpha-linolenic acid (ALA), docosahexaenoic acid (DHA) and medium-chain triglycerides (FA-ADEK) for 12 weeks. The fatty acid profile of erythrocyte membrane phospholipids, dietary intake, plasma antioxidant vitamins and serum gamma-glutamyl transferase (GGT) were evaluated at baseline, 8 and 12 weeks after supplementation. RESULTS: Supplementation with FA-ADEK increased ALA, DHA and eicosapentaenoic acid (EPA) concentrations of erythrocyte membrane phospholipids by 0.040, 1.419 and 0.159%, respectively, compared with ADEK supplementation (-0.007, 0.151 and 0.002%, respectively) after 12 weeks (all P

[Glucocorticoid monotherapy for Cogan syndrome?]. / Glucocorticoid-Monotherapie beim Cogan-Syndrom?

A 27-year-old woman suddenly developed persistent rotatory dizziness with unsteadiness on standing and walking, associated with symptoms relating to the autonomic nervous system, all signs and symptoms disappearing without treatment in 3 days. Ten days before this episode she had noticed progressive bilateral impairment of hearing accompanied by tinnitus. Caloric and audiometric tests confirmed bilateral impairment of the audiovestibular organ. A week later she also developed bilateral iritis and papillitis. The constellation of ocular and audiovestibular signs suggested Cogan's syndrome. Under high-dosage glucocorticoid treatment (initially 1,000 mg/d prednisolone intravenously for 3 days, then 100 mg/d orally in decreasing doses down to 10 mg daily) the ocular signs improved, but the bilateral hearing impairment persisted. A recurrence occurred after 5 months, while on a prednisolone dosage of 10 mg daily, together for the first time with arthralgias, suggesting systemic involvement. Although the symptoms quickly subsided when dosage was increased to 100 mg daily, repeated attempts at dose reduction brought about renewed exacerbation at 70 mg daily. As the necessary high steroid dosage led to severe side effects, an immunosuppressive drug was added (100 mg cyclophosphamide and 20 mg prednisolone, both daily; later 5 mg methotrexate weekly and 4 mg prednisolone every other day). The symptoms had not recurred when re-examined 7 months later.

"Atypical p-ANCA" in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines.

BACKGROUND & AIMS: Atypical "antineutrophil cytoplasmic antibodies" (ANCA) are present in patients with ulcerative colitis (UC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH). Recently, we showed that atypical p-ANCA react with nuclear envelope proteins of neutrophils. Based on this observation, we aimed to characterize the nuclear antigen recognized by atypical p-ANCA. METHODS: We prepared cytoplasmic and nuclear extracts of human neutrophils, human HL-60, and murine 32D myeloid cells. Proteins were resolved by 1- and 2-dimensional gel electrophoresis. Reactive proteins were detected by immunoblotting with sera from 118 individuals (UC, 25; PSC, 28; AIH, 35; disease and normal controls, 30). Atypical p-ANCA (n = 64) were affinity-purified against the reactive protein and investigated for their immunofluorescence pattern using confocal microscopy. RESULTS: Immunoblotting showed reactivity to a myeloid-specific 50-kilodalton nuclear protein with an isoelectric point of pH 6.0 detected in 92% (59 of 64) of the patients with inflammatory bowel or hepatobiliary diseases and atypical p-ANCA. Affinity-purified antibodies against the 50-kilodalton protein gave a nuclear rim-like fluorescence on myeloid cells examined by immunofluorescence microscopy. Affinity-purified antibodies did not recognize antigens in nonmyeloid cells. CONCLUSIONS: Atypical p-ANCA in UC, PSC, or AIH recognize a 50-kilodalton myeloid-specific nuclear envelope protein.

[Stent implantation for the palliative therapy of upper inflow obstruction in bronchial carcinoma]. / Stent-Implantation zur palliativen Therapie der oberen Einflussstauung bei Bronchialkarzinom.

AIM OF STUDY: To analyse results obtained in the palliative treatment of obstruction of the upper inflow veins by stent implantation in patients with bronchial carcinoma. PATIENTS AND METHODS: Stents were implanted in 14 patients with upper venous obstruction due to bronchial carcinoma (three women, eleven men: mean age 64 [48-74] years), 4 of the superior vena cava (SVC), 6 of the SVC and brachiocephalic vein, 4 of the SVC and subclavian vein. To prevent thromboembolic phenomena all patients received heparin in therapeutic doses for 1-3 days from the time of stents implantation. RESULTS: Treatment was successful (regression of the clinical signs) in 12 of the 14 patients. Six patients died, without recurrence of the clinical signs, an average of 141 (10-420) days after the procedure. Mean survival time of the six patients who remained without symptoms was 3 months (longest interval 9 months). In one patient thrombotic occlusion of the SVC occurred 6 days after stent implantation. However, local thrombolysis successfully re-opened the vessel. Renewed upper vein obstruction occurred in two patients during follow-up. None of the stent filaments fractured and there was no stent dislocation. CONCLUSION: With a success rate of 86% stent implantation proved to be a sparing procedure in the palliative treatment of upper inflow vein obstruction, especially in patients with extensive malignant disease.

[The Churg-Strauss syndrome with cerebral seizures and terminal kidney failure]. / Churg-Strauss-Syndrom mit zerebralen Krampfanfällen und terminaler Niereninsuffizienz.

HISTORY AND CLINICAL FINDINGS: A 67-year-old man with known bronchial asthma was admitted to hospital because of deteriorating general state of health, fever, progressive renal failure and confusional states. INVESTIGATIONS: Erythrocyte sedimentation rate was 70/95 mm and the concentration of C-reactive protein raised to 30 mg/dl. WBC count was 19,000/microliter with 39% eosinophilia. Anticytoplasmatic antibodies (cANCA) had a high titre (1:160). On admission the creatinine level was 5.6 mg/dl. Renal biopsy indicated marked glomerular and tubulo-interstitial scarring. Chest radiograms showed transient pulmonary infiltrates. Churg-Strauss syndrome (CSS) was diagnosed on the basis of the clinical and biochemical findings. TREATMENT AND COURSE: Haemodialysis was instituted to counteract the renal failure with water retention. Inflammatory parameters and clinical symptoms rapidly responded to administration of corticosteroids (prednisolone, initially 250 mg/d for 3 days, then 150 mg/d for 5 days followed by slowly decreasing doses). Two weeks after starting prednisolone he had secondary generalised seizures. Magnetic resonance imaging (MRI) of the skull demonstrated marked hyperintense focal changes which in their pattern were characteristic of cerebral vasculitis. As a steroid-refractory condition had to be assumed, cyclophosphamide was also given (100 mg/d). Within 6 weeks the clinical symptoms gradually regressed and the MRI changes became practically normal. CONCLUSION: Early combined immunotherapy should be given if CSS runs a complicated course, rather than the usually recommended corticosteroid monotherapy.

IgA class antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis and autoimmune hepatitis.

Antineutrophil cytoplasmic antibodies (ANCA) of IgG class have been described at high prevalence in autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). Data on IgA class ANCA in these diseases are limited. The aim of this study was to determine the prevalence and fluorescence patterns of IgA class ANCA in AIH and PSC and to examine a relationship between the presence of IgA ANCA and clinical characteristics in these patients. Sera from 35 patients with PSC (21 with concomitant inflammatory bowel disease), 40 patients with AIH and 10 healthy controls were studied. ANCA were detected on ethanol-fixed neutrophils using an indirect immunofluorescence technique. ANCA of the IgA class were found in 20% of sera from patients with PSC and in 50% of AIH sera. The majority of AIH patients with IgA class ANCA showed a 'classical' perinuclear staining pattern, whereas the 'classical' and 'atypical' perinuclear fluorescence patterns were distributed equally in PSC. In sera containing IgG and IgA class ANCA simultaneously, IgG class ANCA showed an 'atypical' pANCA fluorescence pattern whereas IgA class ANCA produced a 'classical' perinuclear staining. The presence of IgA class ANCA was not associated with disease-specific clinical characteristics. IgA class ANCA are more frequently detected in sera of patients with AIH than PSC. The diversity of fluorescence patterns points to different target antigens of IgA class ANCA with distinct subcellular localizations.

Treatment of Barrett's esophagus by endoscopic argon plasma coagulation.

Barrett's esophagus is a premalignant condition characterized by the presence of specialized columnar epithelium in the distal esophagus. Conventional medical or surgical treatments do not consistently lead to a regression of Barrett's epithelium. However, restoration of squamous mucosa can occur in an anacid environment after endoscopic ablation of metaplastic epithelium. We report here on two patients with long-standing history of Barrett's esophagus who were treated with endoscopic argon plasma coagulation. By six months of endoscopic treatment, Barrett's epithelium had regressed by more than 50%, being replaced by apparently normal squamous epithelium in both patients. Extensive histological sampling confirmed the presence of squamous epithelium indistinguishable from normal esophageal mucosa. Both patients were asymptomatic under concomitant therapy with proton pump inhibitors with the exception of slight retrosternal discomfort the day after treatment. This demonstrates that endoscopic argon plasma coagulation may be considered for the treatment of Barrett's esophagus.

Differentiation of antineutrophil nuclear antibodies in inflammatory bowel and autoimmune liver diseases from antineutrophil cytoplasmic antibodies (p-ANCA) using immunofluorescence microscopy.

Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) directed against cytoplasmic proteins of neutrophils have been studied extensively in patients with systemic vasculitides. Recent data indicate that antineutrophil antibodies in sera from patients with chronic inflammatory bowel diseases (IBD) or autoimmune liver disorders, currently called 'atypical p-ANCA', recognize a nuclear target antigen, rendering the term 'ANCA' inaccurate. Specific microscopic criteria to distinguish atypical p-ANCA from p-ANCA are lacking. We used planar and confocal laser scanning indirect immunofluorescence microscopy to examine the labelling characteristics of ethanol-, methanol- and formaldehyde-fixed neutrophils by antineutrophil antibodies in 153 serum samples from patients with IBD, autoimmune liver disorders, systemic vasculitides or healthy blood donors. On ethanol- or methanol-fixed neutrophils, multiple intranuclear fluorescent foci together with either a rim-like peripheral nuclear staining ('type A') or a combined cytoplasmic and peripheral nuclear staining ('type B') was noted exclusively with atypical p-ANCA in sera from patients with IBD or autoimmune liver disorders. Intranuclear foci, which probably corresponded to invaginations of the nuclear envelope, were not labelled by p-ANCA from patients with microscopic polyangiitis or cytoplasmic ANCA (c-ANCA) from patients with Wegener's granulomatosis. On formaldehyde-fixed neutrophils, atypical p-ANCA gave a fine rim-like staining of the nuclear periphery, whereas ANCA diffusely labelled the cytoplasm. To distinguish reliably between the patterns produced by atypical p-ANCA or p-ANCA, particularly p-ANCA, careful indirect immunofluorescence microscopy on ethanol- as well as on formaldehyde-fixed neutrophils is necessary, with particular emphasis on the presence of multiple intranuclear fluorescent foci.

Atypical antineutrophil cytoplasmic antibodies with perinuclear fluorescence in chronic inflammatory bowel diseases and hepatobiliary disorders colocalize with nuclear lamina proteins.

Antineutrophil cytoplasmic antibodies (ANCA) are frequently associated with chronic inflammatory bowel diseases (IBD) and hepatobiliary disorders. However, their target antigens have not been identified yet. Recently, we observed an atypical perinuclear ANCA fluorescence (p-ANCA) together with an intranuclear staining using ANCA-positive sera from patients with IBD and hepatobiliary disorders. This observation suggests that the target antigens are localized within the nucleus of neutrophilic granulocytes. To further investigate this hypothesis, we examined sera from patients with ulcerative colitis, primary sclerosing cholangitis, autoimmune hepatitis or systemic vasculitis on ethanol or formaldehyde-fixed neutrophils using confocal laser scanning microscopy and immunoelectron microscopy. Counterstaining with propidium iodide, a DNA-specific dye, showed that ANCA-positive sera in IBD and heptobiliary disorders react with intranuclear antigens at the nuclear periphery of the neutrophils. Double immunolabeling techniques revealed that nuclear lamina proteins, lamins A, C and B1, and lamin B receptor were colocalized with the antigen(s) recognized by atypical p-ANCA. No colocalization was observed with classical p-ANCA and antibodies against histones (H1-H4). Our study showed that atypical p-ANCA are antinuclear antibodies reactive with granulocyte-specific antigens present in the nuclear lamina.

Three-dimensional magnetic resonance cholangiopancreatography with respiratory triggering in the diagnosis of primary sclerosing cholangitis: comparison with endoscopic retrograde cholangiography.

BACKGROUND AND STUDY AIMS: The purpose of this study was to evaluate the accuracy of respiratory-triggered three-dimensional magnetic resonance cholangiopancreatography (3D-MRCP) for the detection of primary sclerosing cholangitis (PSC) and to compare the specific findings of magnetic resonance cholangiography and endoscopic retrograde cholangiography in patients with PSC. PATIENTS AND METHODS: The MRCP findings were evaluated in 150 patients with clinical symptoms (progressive fatigue, pruritus followed by icterus) and/or elevated values for alkaline phosphatase and serum aspartate transaminase, and occasionally an elevated serum concentration of bilirubin as a sign of cholestasis, who were consecutively referred for magnetic resonance imaging. Two observers independently classified bile duct abnormalities and established the MRCP diagnosis in a consensus reading. The results of MRCP were compared with the definitive diagnosis, which was based on the clinical history and laboratory and histological data, as well as on endoscopic retrograde cholangio-pancreatography (ERCP) findings. In a second step, the observers compared the delineation of the biliary system and morphological findings using MRCP and ERCP in patients with confirmed PSC. RESULTS: Diagnostic examinations were obtained in 146 of the 150 MRCPs (97 %). The diagnosis of PSC was confirmed by clinical data and ERCP in 34 of these 150 patients (23 %). The sensitivity and specificity of MRCP for diagnosing PSC were 88 % (29 of 33) and 99 % (108 of 109), respectively. MRCP and ERCP yielded similar scores for the delineation of the biliary system (P = 0.2) in patients with PSC. However, different bile duct abnormalities leading to the diagnosis of PSC were depicted by MRCP and ERCP; more bile duct stenoses and pruning were seen with ERCP and more skip dilatation with MRCP (P < 10(-4)). CONCLUSION: In patients with PSC, MRCP is a highly sensitive method and its diagnostic accuracy is comparable to that of ERCP.