Dominik M. Alscher

Magnetic Resonance Assessment and Therapy Monitoring of Cardiac Involvement in Churg-Strauss Syndrome

A 39-year–old man, with a temperature of 38.5°C and sinus tachycardia, was admitted for work-up of chest pain. He had a history of asthma, recurrent pneumonia, sinusitis, and nasal polyposis. Clinical examinations, ECG (Figure 1) and chest x-ray (Figure 2) on admission were suspicious for perimyocarditis. Routine blood analysis revealed an elevated erythrocyte sedimentation rate (88 mm/h; normal <15 mm/h) and a normal leukocyte count (7200/mm3) with 21% eosinophilic granulocytes (normal 1% to 6%). Levels of C-reactive protein and immunoglobulin E were elevated at 14.0 mg/dL (normal 0.1 to 0.5 mg/dL) and 237 U/mL (normal <100 U/mL), respectively. Thus, Churg-Strauss syndrome with perimyocardial involvement was suspected. Figure 1. Twelve-lead ECG obtained at initial presentation in our emergency room, demonstrating ST-abnormalities suspicious for perimyocarditis. Figure 2. Frontal posterior–anterior chest x-ray on admission. Note the enlarged pulmonary hila, as well as the relation of the cardiac silhouette to the lateral distance (16 cm/32.5 cm), suggesting mild cardiac enlargement, pericardial effusion, or a combination of these conditions. Because echocardiography could not provide any information on myocardial involvement in this case (Figure 3; for full-motion images, see Movie I in the online-only Data Supplement), the patient was referred for cardiovascular magnetic resonance imaging (CMR; 1.5 Tesla Sonata, Siemens Medical Systems, Erlangen, Germany). Cine images were acquired using fast-gradient echo steady-state free precession …

Improved estimation of glomerular filtration rate by serum cystatin C in preventing contrast induced nephropathy by N-acetylcysteine or zinc—preliminary results

BACKGROUND Prevention of contrast media (CM) induced nephropathy (CIN) by prophylaxis (e.g. N-acetylcysteine; NAC) is controversially discussed. Up to now, assessment of kidney function has been based on measurements of serum creatinine, although this biomarker has several limitations. We investigated NAC and zinc (Zn) for the prevention of CIN by monitoring creatinine and cystatin C. METHODS In a prospective, placebo-controlled, double blind trial, patients with moderately impaired kidney function receiving low-osmolar, non-ionic CM were randomly assigned to an oral treatment for 2 days with 1.2 g/day of NAC (n = 19), for 1 day with 60 mg/day of Zn (n = 18) or placebo (n = 17). All patients received peri-procedurally 1 ml/kg/h of 0.45% saline for 24 h. At baseline, prior to exposure of CM, 2 and 6 days after CM, creatinine and cystatin C were measured. RESULTS There was no difference in the incidence of CIN, but a significant drop in creatinine (P < 0.05) was observed in all patients during volume expansion. Creatinine showed no increase after CM and it was normalized to the baseline values in all groups at the study end. In contrast, 2 days after CM there was a significant rise in cystatin C in the Zn (P = 0.012) and the placebo (P = 0.041) group, whereas NAC prevented this deterioration of kidney function. CONCLUSIONS Cystatin C seems to reflect CM-induced changes in kidney function better than creatinine. NAC and Zn have no effect in preventing CIN by the standard definition, but based on cystatin C we can confirm a preventive effect of NAC. It appears mandatory to assess kidney function by cystatin C in CIN intervention trials, because relying on creatinine can be misleading.

Podoplanin-positive cells are a hallmark of encapsulating peritoneal sclerosis

BACKGROUND Encapsulating peritoneal sclerosis (EPS) and simple peritoneal sclerosis are important complications of long-term peritoneal dialysis (PD). Podoplanin is expressed by mesothelial cells and lymphatic vessels, which are involved in inflammatory reactions in the peritoneal cavity. METHODS We studied 69 peritoneal biopsies from patients on PD (n = 16), patients with EPS (n = 18) and control biopsies taken at the time of hernia repair (n = 15) or appendectomy (n = 20). Immunohistochemistry was performed to localize podoplanin. Additionally, markers of endothelial cells, mesothelial cells, myofibroblasts (smooth muscle actin), proliferating cells, and double labelling for smooth muscle actin/podoplanin were used on selected biopsies. RESULTS Podoplanin was present on the endothelium of lymphatic vessels in the submesothelial fibrous tissue and on mesothelial cells. In patients on PD and in biopsies with appendicitis, the mesothelial cells demonstrated a cuboidal appearance and circumferential podoplanin staining, with gaps between the cells. The number of lymphatic vessels was variable, but prominent at sites of fibrosis. In patients with EPS, a diffuse infiltration of podoplanin-positive cells with a fibroblastic appearance was present in 15 out of 18 biopsies. This pattern was focally present in 3 out of 16 on PD and none in the 35 controls. The podoplanin-positive cells did not express the endothelial marker or the mesothelial marker (calretinin). CONCLUSIONS EPS is characterized by a population of podoplanin and smooth muscle actin double-positive cells. Podoplanin might be a suitable morphological marker supporting the diagnosis and might be involved in the pathogenesis of EPS.

Hepatic expression of galectin‐3 and receptor for advanced glycation end products in patients with liver disease

Background: Advanced glycation end products (AGEs) are a heterogeneous group of glycosylated proteins (of which carboxymethyl-lysine (CML) is the most common) which accumulate during ageing processes and play an important role in the pathogenesis of a variety of chronic diseases. Impaired hepatic function might result in elevated levels of AGEs, as the liver represents the major site of AGE metabolism. The actions of AGEs are mediated by various receptors, among which the AGE-receptor complex (including galectin-3 as an essential part) is thought to have a cytoprotective effect, and receptor for advanced glycation end product (RAGE) a cytotoxic effect. Aim: To assess the relationship between CML and expression of galectin-3 and RAGE in different histological structures in biopsy specimens from patients with varying degrees of liver impairment. Method: Immunohistochemical staining of 164 biopsies from patients with varying degrees of liver impairment was performed to determine the levels of CML, galectin-3 and RAGE in hepatocytes, Kupffer cells and bile ducts by a semiquantative score. Results: Independent of diagnosis, CML and RAGEs were detected in hepatocytes, whereas galectin-3 was present only in hepatocytes of cirrhotics. By contrast, CML and galectin-3 were highly expressed in Kupffer cells (well correlating levels, highest scores in cholestasis) whereas expression of RAGEs was not significant. All three assessed biochemical markers showed their highest levels of expression/detection in bile ducts. Conclusion: These findings indicate an increased susceptibility of hepatocytes to the detrimental effects of AGEs and underline the protective function of Kupffer cells. Furthermore, the biliary system seems to play an important role in the disposition of AGEs.

Induction of Metallothionein in Proximal Tubular Cells by Zinc and Its Potential as an Endogenous Antioxidant

Background: This study was undertaken to gain further insights into the expression of metallothionein (MT) in kidney, to define the necessary dosage of a metal (zinc) to achieve induction of MT and to evaluate the antioxidative potential of MT in comparison to other more common antioxidative therapeutics, like N-acetyl-L-cysteine (NAC), and endogenous molecules, like glutathione. Methods: MT was measured in renal specimens from cadaver kidneys from patients with chronic diseases (n = 76) and controls (n = 21) by immunohistochemistry. In addition, induction experiments were performed in cell cultures of proximal tubular cells (LCC-PK1) and MT measured on the RNA and protein level (immunohistochemistry, Western and dot blotting). Antioxidative potential of MT was compared to NAC and glutathione. Results: MT was restricted to tubular cells with no differences between controls and patients. Zn caused a dose-dependent increase of MT on the RNA as well as on the protein level (RNA (ratio MT/histone 3.3): control 0.34 ± 0.12; Zn 17 µM 0.65 ± 0.26; Zn 35 µM 1.25 ± 0.43 (p < 0.05), Zn 52 µM 1.35 ± 0.46 (p < 0.05), and protein: 5.8-fold increase from 47 ± 13 mg/g total protein (n = 6) to 272 ± 140 mg/g total protein (n = 6)). The antioxidative effect of MT was equal to NAC and glutathione. Conclusions: Induction of renal MT by zinc is easily achievable and might be an interesting therapeutic and preventive tool against oxidative stress.

A new lactate-based, plasticizer-free, neutral peritoneal dialysis fluid provided in a two-compartment system: effect on peripheral leukocyte function.

Background: A new neutral peritoneal dialysis fluid (PDF; Balance®) provided in a two-compartment bag (pH 7.4, no plasticizers, minimal glucose degradation products – GDP) was investigated in comparison with a neutral control (Hanks’ balanced salt solution with gelatin 0.1%) and other PDFs with standard properties and plasticizers (Andy plus®, pH 5.2, GDP), plasticizer free (stay safe®, pH 5.2, GDP), and in addition plasticizer free after sterile filtration instead of heat sterilization (pH 5.2) regarding the function of peripheral blood leukocytes. Methods: Blood was drawn from 12 volunteers, and blood monocytes (MN) and polymorphonuclear leukocytes (PMNL) were collected. The cells were incubated for 30 min in control medium and the PDFs: glucose 1.5% (83 mmol/l) and 4.25% (238 mmol/l). Respiratory burst of cells was evaluated by chemiluminescence and superoxide (SO) generation after stimulation with phorbol myristate acetate. Results: In comparison with the control medium, incubation of MN in the two-compartment PDF showed preservation of respiratory burst. In contrast, the incubation of MN in standard PDF and plasticizer-free PDF showed impaired functions. The same was found for PMNL. SO anion measurement in MN and PMNL after incubation in the new two-compartment PDF also showed preservation of cell function in comparison with the control medium. The incubation of PMNL in standard PDF and plasticizer-free PDF with a high glucose content showed depressed SO anion generation. Conclusions: These in vitro data demonstrate a better preservation of in vitro phagocyte function with adaptation of pH and reduction of glucose, GDP, and plasticizers in PDFs. The best results are achieved with the two-compartment, lactate-based neutral PDF.

Cure of lifelong fatigue by calcium supplementation

A 56-year-old woman was referred to our department of gynaecology in December, 1999, for operation on an ovarian cyst. A low preoperative calcium (1·40 mmol/L, [normal range 1·90–2·70] and ionised calcium (0·69 mmol/L [1·15–1·30]) and a raised creatinine (239 mol/L [40-100] troubled the anaesthestist. He referred her to a nephrologist before the operation. In her past medical history she had had life-long fatigue and depression. A dentist had diagnosed rickets and another doctor had diagnosed impaired kidney function with renal dysplasia on the right side. The patient had no history of thyroidectomy. On physical examination, the patient had no teeth, was deaf (apparently since birth), and had micrognathia. Further investigations showed a parathyroid hormone in the lower normal range (1·1 pmol/L [1·1–6·9]. Vitamin D and metabolites were in the normal range, as were thyroid stimulating hormone and phosphate. A 24-h urine collection showed a reduced calcium excretion (0·5 mmol/24 h [normal range 2·5–10]); the phosphate excretion was normal. The creatinine-clearance was reduced (31 mL/min). Adominal ultrasound showed a small right kidney (73 mm) and dilatation of the ureter on the right (10 mm). The left kidney size was in the lower normal range.

Pacemaker infection with propionibacterium and a nephritic sediment.

Like any other implanted foreign body, the different parts of pacemakers (pulse generator pocket, epicardial or transvenous leads) can become infected. Staphylococcus aureus and coagulase-negative staphylococci are the causative organisms in most of the cases (65 â 75%), propionibacterium is described to be involved in only 1% of cases. This report describes a case of nephritic sediment in a young female patient with a pacemaker implantation 9 years ago because of a third degree atrioventricular block, in which a battery exchange was necessary 2.5 years ago. This young patient was referred from a nephrologist for renal biopsy because of a nephritic sediment and diffuse complaints including low-grade fever with a suspected underlying autoimmune disease. The laboratory examinations were all negative with the exception of a diminished C3 complement level. Blood cultures were positive for propionibacterium, but the microbiologists were considering it as a contamination. 11 more blood cultures collected thereafter were all positive and a transesophageal ultrasound revealed a small vegetation at 1 of the transvenous electrodes of the pacemaker. Because of a penicillin allergy she was treated with clindamycin, and the blood cultures were negative after a few days. After a full course (7 weeks) of antibiotic treatment the C3 complement level normalized and a series of 10 blood cultures remained negative 10 â 15 days after discontinuation of antibiotic therapy. Discussing all the differential diagnoses of a nephritic sediment combined with hypocomplementemia, positive blood cultures and a vegetation on a pacemaker electrode in the transesophageal ultrasound, the diagnosis of an immune complex glomerulonephritis due to a propionibacterium pacemaker infection needs no confirmation by renal biopsy.

Therapie der Hepatitis C

ZusammenfassungZiel dieser Arbeit ist zum einen ein Fortschrittsbericht der Therapie der Hepatitis C insbesondere mit Interferon-α. Zum anderen wird aus einer großen Zahl von Publikationen das für die Therapie Gesicherte aufgearbeitet und hieraus Empfehlungen für das praktische Vorgehen abgeleitet. Ein dritter Schwerpunkt der Übersicht gilt neuen, im Stadium der Erprobung befindlichen Therapieformen sowie zur Zeit noch nicht eindeutig zu beurteilenden Aspekten zur Therapie der chronischen Hepatitis C.Bei der vergleichsweise selten erfaßten akuten Phase einer Hepatitis C wird durch eine Behandlung mit Interferon-α (dreimal drei Mio E/Woche über einen Zeitraum von drei bis vier Monaten) der Anteil der Patienten, bei denen eine Elimination von HCV-RNA aus dem Serum erreicht wird, erhöht. Bei Patienten mit chronischer Hepatitis C ist nach Indikationsstellung zur Therapie außerhalb von Studien ein Standardschema einer Monotherapie mit rekombinantem Interferon-α zu empfehlen. Als Dosis sollten fünf bis sechs Mio E dreimal/Woche für die ersten zwölf bis 16 Wochen angestrebt werden. Anschließend sollte die Behandlung mit drei Mio E dreimal wöchentlich fortgesetzt werden. Die Therapiedauer sollte in der Regel zwölf Monate betragen. Ein langfristiger oder dauerhafter Therapieerfolg, gemessen an einer anhaltenden Normalisierung der Transaminasewerte und einem negativen HCV-RNA-Befund im Serum, ist bei unausgewählten Patientengruppen bei etwa 20% der behandelten Patienten zu erwarten. Wichtige Faktoren, die den durchschnittlichen Therapierfolg beeinflussen, wie der HCV-Genotyp, der Virustiter im Serum, die Erkrankungsdauer, ein höherer Eisengehalt in der Leber und das Vorliegen einer Zirrhose, werden besprochen. Bei Nicht-Ansprechen und bei erneutem Anstieg der Transaminasen während und nach Beendigung der Therapie existieren noch keine klaren Empfehlungen. Die Kombinationstherapie von INFα mit anderen Medikamenten, wie Nukleotidanaloga (Ribavirin), nicht-steroidalen Antirheumatika und Ursodeoxycholsäure (UDCS) werden in kontrollierten klinischen Studien erprobt.SummaryThe purpose of this review is an update of the therapy of hepatitis C especially with Interferon-α. From the large number of publications on this topic the established facts were worked out. Taking these facts as a base guidelines for the therapy in practical use were defined. In addition the aspects of therapeutic strategies of chronic hepatitis C which until now can not definitely be judged are discussed.In the relatively few patients in whom hepatitis C is diagnosed already in the acute phase. Interferon-α-treatment (3×3 million units 3 times a week) for 3 to 4 months increases the percentage of patients in whom HCV-RNA in serum is climinated.In patients with chronic hepatitis C, after decision finding for treatment, a standard scheme is recommended which consists of a monotherapy with recombinant Interferon-α. The dosage of Interferon-α is in the first 12 to 16 weeks 5 up to 6 million units given 3 times a week. For the further therapy 3 million units 3 times a week seems to be appropriate. The recommended duration of Interferon-α-therapy is 12 months. A long-term benefit of about 20% can be achieved in unselected groups of patients when judged on the permanent normalisation of serum transaminases and elimination of HCV-RNA in the serum. Important factors which may influence the probability of a sustained response, like HCV genotype, virus titer in serum, duration of the disease, high hepatic iron content and the presence of cirrhosis, are discussed. Up to now there exist no reliable guidelines in the case of a “no change” situation and for patients with a flare-up of inflammatory activity during or after therapy. Combination therapy of Interferon-α with other drugs like analogous of nucleotides (for example ribavarin), non steroidal antirheumatic drugs and ursodesoxycholic acid (UDCA) have still to be evaluated in controlled clinical trials.

Gastrointestinal involvement in granulomatosis with polyangiitis and microscopic polyangiitis: histological features and outcome

Gastrointestinal (GI) involvement in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is rare.