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Biomedical subjects

Christoph Wanner

Publications and source records attributed to Christoph Wanner.

At least 37 records · Page 2Linked to original sources
PubMed2005

Beta(2)-microglobulin removal by extracorporeal renal replacement therapies.

There is increasing evidence that end-stage renal disease patients with lower beta(2)-microglobulin plasma levels and patients on convective renal replacement therapy are at lower mortality risk. Therefore, an enhanced beta(2)-microglobulin removal by renal replacement procedures has to be regarded as a contribution to a more adequate dialysis therapy. In contrast to high-flux dialysis, low-flux hemodialysis is not qualified to eliminate substantial amounts of beta(2)-microglobulin. In hemodialysis using modern high-flux dialysis membranes, a beta(2)-microglobulin removal similar to that obtained in hemofiltration or hemodiafiltration can be achieved. Several of these high-flux membranes are protein-leaking, making them suitable only for hemodialysis due to a high albumin loss when used in more convective therapy procedures. On-line hemodiafiltration infusing large substitution fluid volumes represents the most efficient and innovative renal replacement therapy form. To maximize beta(2)-microglobulin removal, modifications of this procedure have been proposed. These modifications ensure safer operating conditions, such as mixed hemodiafiltration, or control albumin loss at maximum purification from beta(2)-microglobulin, such as mid-dilution hemodiafiltration, push/pull hemodiafiltration or programmed filtration. Whether these innovative hemodiafiltration options will become accepted in clinical routine use needs to be proven in future.

Hemodiafiltration↗
PubMed2005

Native C-reactive protein increases whereas modified C-reactive protein reduces atherosclerosis in apolipoprotein E-knockout mice.

BACKGROUND: C-reactive protein (CRP) may have proatherogenic but also vasoprotective properties. We tested the hypothesis that the configuration of CRP (pentameric, or native [nCRP], versus monomeric, or modified [mCRP]) determines these different characteristics in an in vivo model. METHODS AND RESULTS: We investigated the effects of human nCRP and mCRP on the development of atherosclerosis in apolipoprotein E-knockout (ApoE(-/-)) mice. Treatment with nCRP for 8 weeks (2.5 mg/kg SC weekly) resulted in a 4-fold-higher mean aortic plaque area in 14-week-old female ApoE(-/-) mice compared with the saline controls. In contrast, mean plaque size was decreased by approximately 50% in mCRP-treated ApoE(-/-) mice (2.5 mg/kg SC weekly). Using immunohistochemistry, we report the natural presence of the mCRP antigen in saline controls. mCRP antigen was expressed in smooth muscle cells and extracellularly in the vicinity of the plaques to a similar level in both CRP-treated groups and saline controls. mCRP and ApoB colocalized with macrophages and were equally upregulated in all aortic plaques. Vascular cell adhesion molecule expression was increased, and CD154 and intercellular adhesion molecule showed a trend for higher expression in nCRP-treated compared with mCRP-treated mice. CD154 expression in the vessel wall and plaque size correlated significantly. mCRP-treated ApoE(-/-) exhibited higher serum levels of the antiinflammatory interleukin-10 compared with the other 2 groups. CONCLUSIONS: Here, we show that mCRP and nCRP have opposite effects on atherosclerosis in ApoE(-/-) mice. These data may explain in part the conflicting activities previously reported for CRP in models of atherogenesis.

Animals↗
PubMed2005

Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.

BACKGROUND: Statins reduce the incidence of cardiovascular events in persons with type 2 diabetes mellitus. However, the benefit of statins in such patients receiving hemodialysis, who are at high risk for cardiovascular disease and death, has not been examined. METHODS: We conducted a multicenter, randomized, double-blind, prospective study of 1255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis who were randomly assigned to receive 20 mg of atorvastatin per day or matching placebo. The primary end point was a composite of death from cardiac causes, nonfatal myocardial infarction, and stroke. Secondary end points included death from all causes and all cardiac and cerebrovascular events combined. RESULTS: After four weeks of treatment, the median level of low-density lipoprotein cholesterol was reduced by 42 percent among patients receiving atorvastatin, and among those receiving placebo it was reduced by 1.3 percent. During a median follow-up period of four years, 469 patients (37 percent) reached the primary end point, of whom 226 were assigned to atorvastatin and 243 to placebo (relative risk, 0.92; 95 percent confidence interval, 0.77 to 1.10; P=0.37). Atorvastatin had no significant effect on the individual components of the primary end point, except that the relative risk of fatal stroke among those receiving the drug was 2.03 (95 percent confidence interval, 1.05 to 3.93; P=0.04). Atorvastatin reduced the rate of all cardiac events combined (relative risk, 0.82; 95 percent confidence interval, 0.68 to 0.99; P=0.03, nominally significant) but not all cerebrovascular events combined (relative risk, 1.12; 95 percent confidence interval, 0.81 to 1.55; P=0.49) or total mortality (relative risk, 0.93; 95 percent confidence interval, 0.79 to 1.08; P=0.33). CONCLUSIONS: Atorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in patients with diabetes receiving hemodialysis.

Aged↗
PubMed2005

L-Arginine does not affect renal morphology and cell survival in ischemic acute renal failure in rats.

BACKGROUND: L-Arginine (L-Arg), a substrate of nitric oxide synthases, improves renal function in ischemic acute renal failure (iARF). We evaluated whether L-Arg improves renal morphology and cell survival in the course of iARF. METHODS AND RESULTS: iARF was induced in rats by bilateral clamping of renal arteries for 45 min. L-Arg was applied intraperitoneally during clamping, and orally during 14 days of follow-up. Morphology and cell survival of renal cortical and medullar tissue was analyzed on days 1, 3, 7, and 14 of follow-up, using toluidine blue staining and immunohistochemistry of perfusion-fixated tissue, and Western blot analysis of tissue homogenate. Renal tubular injury showed typical features of necrosis and was most severe on days 1 and 3 after clamping, predominantly in S3 segments, with almost complete recovery by day 14. Enhanced medullar monocyte infiltration, determined by ED-1 expression as well as by immunohistochemistry, and enhanced expression of proliferating cell nuclear antigen (PCNA), indicative of proliferation and regeneration, accompanied these morphological changes. Compared to controls, L-Arg had no impact on renal morphology, ED-1, and PCNA expression. Furthermore, expression of markers of apoptosis Bcl-2, Bax, and cleaved caspase-3 was only slightly increased in iARF rats, compared to sham-operated animals, and was also not influenced by L-Arg. CONCLUSION: Despite its repeatedly reported positive impact on renal function as also shown in our model, L-Arg does not alter cell death and proliferation in the course of iARF in our model. Thus, different mechanisms have to be considered, in particular improved intrarenal hemodynamics.

Acute Kidney Injury↗
PubMed2005

Sample sizes for clinical trials with time-to-event endpoints and competing risks.

We consider clinical trials where the time to occurrence of events in the presence of competing risks is the primary endpoint for treatment evaluation. The number of events with regard to the defined primary endpoint required to ensure the specified power can be calculated according to Schoenfeld's formula like in classical survival studies. However, determination of the number of patients that have to be recruited to observe the calculated number of events requires specification of the length of the accrual period, the trial duration and assumptions about the event-specific hazard functions. Information from previous studies about expected failure rates for the reference treatment is useful and can be translated into assumptions about the appropriate model parameters. A formula for sample size computation is presented for two competing outcome states. Nomograms help to communicate different alternatives of duration and size of the trial to interdisciplinary committees whose members plan and monitor the clinical trial. The 4D trial (Die Deutsche Diabetes Dialyse Studie) designed to compare lipid lowering treatment with HMG-CoA reductase inhibitor atorvastatin with placebo in type 2 diabetic patients on hemodialysis with respect to time to the composite event "cardiovascular death or non-fatal myocardial infarction" is used as an example to outline the statistical methods.

Clinical Trials Data Monitoring Committees↗
PubMed2005

The variation of morphological and functional cardiac manifestation in Fabry disease: potential implications for the time course of the disease.

AIMS: The aim of this clinical cross-sectional study was to investigate the cardiac interrelation of morphological and functional abnormalities in patients with Fabry disease. METHODS AND RESULTS: Fifty-one patients (5-78 years) were compared with 25 controls (8-77 years). In all subjects, end-diastolic thickness of the left ventricle was measured by echocardiography and ultrasonic peak systolic strain rate (SR) was extracted to assess regional myocardial function. Magnetic resonance imaging was performed to assess late-enhancement for the detection of myocardial fibrosis in Fabry patients (n=39). In patients, women <20 years of age had no hypertrophy, no late-enhancement, and normal radial and longitudinal function (SR longitudinal=-1.7+/-0.5 s(-1); P=n.s. compared with controls). Ten women, >20 years of age, had no hypertrophy, no late-enhancement, normal radial and longitudinal function in the septal wall, but reduced longitudinal function in the lateral wall (SR=-1.4+/-0.5 s(-1)). All male patients without hypertrophy and no late-enhancement had normal radial function but reduced longitudinal function in both the septal and lateral walls (SR=-1.3+/-0.3 s(-1)). Patients with hypertrophy but without late-enhancement (n=13) had reduced radial and longitudinal function. Twelve patients displaying hypertrophy and late-enhancement had severely reduced radial and longitudinal function (SR=-1.1+/-0.5 s(-1)). Two of them with the worst impairment of regional function (SR=-0.8+/-0.6 s(-1)) died in the follow-up period. CONCLUSION: These results illustrate the variation of morphological changes and its functional consequences in Fabry cardiomyopathy.

Adolescent↗
PubMed2005

Optimal treatment of renal anaemia (OPTA): improving the efficacy and efficiency of renal anaemia therapy in haemodialysis patients receiving intravenous epoetin.

The medical care of renal anaemia has received much attention over the past decade, as nephrologists have recognized the increased therapeutic value of erythropoiesis-stimulating agents. The European Best Practice Guidelines and the US National Kidney Foundation's Kidney Disease Outcome Quality Initiative Guidelines have provided evidence-based advice on the optimal treatment of renal anaemia, and have recommended a target haemoglobin (Hb) level of 11 g/dl or 11-12 g/dl. Achieving this target Hb level has been shown to improve quality of life and reduce the rate of hospitalization; there is also good evidence to suggest that achieving adequate Hb levels reduces morbidity and mortality in patients with end-stage renal disease. In recent years, a number of factors have been identified that may counteract the positive action of epoetin therapy. These treatment-influencing factors include inadequate haemodialysis, absolute and functional iron deficiency, anticoagulant use, inflammation and infection. Each factor on its own may result in a substantial decrease in Hb levels, or an increase in epoetin requirements of up to 100%. Therefore, optimal and cost-effective treatment can only be achieved by adequately managing all of the factors that potentially can influence anaemia in patients with chronic kidney disease. Large-scale, cross-sectional surveys, such as the European Survey on Anaemia Management and the Dialysis Outcomes and Practice Patterns Study, have shown that there is still room for improving the efficacy and efficiency of anaemia therapy. The Optimal Treatment of Renal Anaemia (OPTA) initiative aims to help both physicians and nurses improve renal anaemia management by "translating" the standards set in published guidelines into practical clinical advice.

Aged↗
PubMed2005

Endothelin B receptor-deficient mice develop endothelial dysfunction independently of salt loading.

BACKGROUND: Rodents without a functional endothelin B (ETB) receptor develop salt-sensitive hypertension. The underlying mechanisms, however, are so far unknown. The ETB receptor is involved in endothelial function by modulating the activity of the endothelial nitric oxide synthesis as well as contributing to the control of endothelial prostacyclin synthesis. In the present study, we analysed whether salt alters endothelial function in rescued ETB receptor-deficient mice. We used mice with a rescue of the lethal phenotype of an ETB knockout. These mice were generated by crossbreeding ETB mice with dopamine-hydroxylase ETB transgenic mice. METHODS: Adult rescued ETB-deficient mice were kept in parallel with wild-type control animals for 15 days on standard (0.2% NaCl) or salt-enriched (4% NaCl) chow, respectively. Systolic blood pressure was measured by the tail cuff method and endothelium-dependent and endothelium-independent vascular function was assessed in isolated aortic rings under isometric conditions. RESULTS: Systolic blood pressure increased on salt-enriched chow in ETB receptor-deficient mice (166 +/- 12 mmHg), but neither in wild-type mice on high-salt diet (128 +/- 11 mmHg; P < 0.05) nor in ETB receptor-deficient mice on standard chow. The heart rate was similar in all groups at any point of time. Endothelium-dependent relaxation was impaired in ETB receptor-deficient mice (74 +/- 3 versus 96 +/- 5% of preconstriction for wild-type mice; P < 0.05) and was not significantly affected by a salt-enriched diet. Endothelium-independent relaxation was similar among all groups. Contractions to endothelin-1 were not significantly influenced by preincubation with the ETB receptor antagonist BQ-788, but were completely blunted by preincubation with the ETA receptor antagonist BQ-123 in all animals. CONCLUSION: Rescued ETB receptor-deficient mice develop salt-sensitive hypertension. Nevertheless, in this animal model of ETB receptor deficiency, endothelial function is impaired independent of salt-enriched diet or hypertension. This indicates that, in this model, salt-induced hypertension is not mediated by endothelial dysfunction.

Animals↗
PubMed2004

Randomized controlled trial on the efficacy and safety of atorvastatin in patients with type 2 diabetes on hemodialysis (4D study): demographic and baseline characteristics.

Patients with type 2 diabetes on dialysis are at a substantially increased risk of cardiovascular and cerebrovascular diseases. Dyslipidemia characterized by moderately elevated low-density lipoprotein cholesterol and high triglycerides and low high-density lipoprotein cholesterol levels is common in this population. We hypothesized that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors would reduce vascular morbidity and mortality in this patient group. The 'Deutsche Diabetes Dialyse Studie' (4D study) is a prospective, randomized, double-blind study involving 178 dialysis centers throughout Germany. Between March 1998 and October 2002, 1,255 patients were randomized to either atorvastatin 20 mg or placebo; 677 men and 578 women, aged 30-83 years, have been enrolled. The study will be terminated as soon as the predefined number of 424 patients with primary combined end points (i.e., cardiovascular death, nonfatal myocardial infarction, or fatal/nonfatal stroke) will have occurred. The total cohort had the following characteristics at baseline: the mean age was 65.7 years, 54% were men, 89% had a history of hypertension, 21% had coronary artery disease, 17.8% had a history of stroke or a transient ischemic attack, and 45% suffered from peripheral arterial disease. The mean time interval between the diagnosis of diabetes and the onset of dialysis was 17.4 years. On average, the patients were on hemodialysis for 8.3 months. Mean lipid and lipoprotein levels were: total cholesterol 219 +/- 43 mg/dl, low-density lipoprotein cholesterol 126 +/- 30 mg/dl, high-density lipoprotein cholesterol 36 +/- 13 mg/dl, and triglycerides 264 +/- 167 mg/dl. The results of the study will provide important information on the efficacy and safety of atorvastatin to support its use in patients with an impaired renal function who are at a high risk of vascular morbidity and mortality.

Adult↗
PubMed2004

Effect of dialysis flux and membrane material on dyslipidaemia and inflammation in haemodialysis patients.

BACKGROUND: Dyslipidaemia, inflammation and oxidative stress are prominent risk factors that potentially cause vascular disease in haemodialysis patients. Dialysis modalities affect uraemic dyslipidaemia, possibly by modifying oxidative stress, but the effects of dialyser flux and membrane material on atherogenic remnant particles and oxidized low-density lipoproteins (LDL) are unknown. METHODS: We performed a randomized crossover study in 36 patients on haemodialysis to analyse the effect of dialyser flux and membrane material on plasma lipids, apolipoproteins and markers of inflammation and oxidative stress. Stable patients on low-flux dialysis with polysulphone for >/=6 weeks were assigned to high-flux polysulphone or high-flux modified cellulose with similar dialyser surface area and permeability characteristics and crossed over twice every 6 weeks. RESULTS: Thirty patients completed the study per protocol. Treatments with high-flux polysulphone and modified cellulose lowered serum triglyceride (by 20% and 10%, respectively; P<0.05) and remnant-like particle cholesterol by 32% (P<0.001) and 11% (NS) after the first 6 weeks of treatment. Oxidized LDL decreased significantly with high-flux polysulphone, but not with modified cellulose. Apolipoproteins CII and CIII were reduced, whereas the ratio CII/CIII was increased (all P<0.05). Acute-phase proteins and LDL and high-density lipoprotein cholesterol remained unaffected. CONCLUSIONS: This randomized crossover study demonstrates a potent effect of high-flux haemodialysis on uraemic dyslipidaemia. Polysulphone membrane material showed superiority on oxidatively modified LDL, an indicator of oxidative stress in haemodialysis patients.

Aged↗
PubMed2004

Advanced renal insufficiency in a 34-year-old man with Lowe syndrome.

Lowe syndrome, or oculocerebrorenal syndrome of Lowe (OCRL), is a rare X-chromosomal disorder characterized by renal dysfunction, congenital cataract, and, in the majority of cases, mental retardation. Although gradual loss of renal function has been seen in most patients, age of onset of deterioration in renal function and its severity and course over time in adult patients have not been documented in detail. We report a 34-year-old man with OCRL without histological changes in renal tissue at the ages of 5 and 8 years, whereas at the age of 29 years, focal and segmental glomerulosclerosis and tubular atrophy were found. During subsequent follow-up of 5 years, progressive loss of renal function occurred, and end-stage renal failure can be expected in a few years. Clinical diagnosis was strongly supported by detecting a nucleotide substitution (IVS19+1g-->a) in the evolutionarily strictly conserved splice consensus sequence of intron 19 of the OCRL1 gene, which may interfere with normal splicing. Clinical course, possible molecular consequences of this novel mutation, and correlation between genotype and phenotype are discussed.

Adult↗
PubMed2003

Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study.

BACKGROUND: Enzyme replacement therapy (ERT) has been shown to enhance microvascular endothelial globotriaosylceramide clearance in the hearts of patients with Fabry disease. Whether these results can be translated into an improvement of myocardial function has yet to be demonstrated. METHODS AND RESULTS: Sixteen patients with Fabry disease who were treated in an open-label study with 1.0 mg/kg body weight of recombinant alpha-Gal A (agalsidase beta, Fabrazyme) were followed up for 12 months. Myocardial function was quantified by ultrasonic strain rate imaging to assess radial and longitudinal myocardial deformation. End-diastolic thickness of the left ventricular posterior wall and myocardial mass (assessed by magnetic resonance imaging, n=10) was measured at baseline and after 12 months of ERT. Data were compared with 16 age-matched healthy controls. At baseline, both peak systolic strain rate and systolic strain were significantly reduced in the radial and longitudinal direction in patients compared with controls. Peak systolic strain rate increased significantly in the posterior wall (radial function) after one year of treatment (baseline, 2.8+/-0.2 s(-1); 12 months, 3.7+/-0.3 s(-1); P<0.05). In addition, end-systolic strain of the posterior wall increased significantly (baseline, 34+/-3%; 12 months, 45+/-4%; P<0.05). This enhancement in radial function was accompanied by an improvement in longitudinal function. End-diastolic thickness of the posterior wall decreased significantly after 12 months of treatment (baseline, 13.8+/-0.6 mm; 12 months, 11.8+/-0.6 mm; P<0.05). In parallel, myocardial mass decreased significantly from 201+/-18 to 180+/-21 g (P<0.05). CONCLUSIONS: These results suggest that ERT can decrease left ventricular hypertrophy and improve regional myocardial function.

Adult↗
PubMed2003

Identification of a new tumor suppressor gene located at chromosome 8p21.3-22.

Transformation of normal cells into malignant tumor cells, a process termed carcinogenesis, depends on progressive acquisition of genetic alterations. These result in activation of protooncogenes or inactivation of tumor suppressor genes responsible for the loss of proliferative control in tumor cells and the failure to undergo cellular differentiation. The aim of our study was the identification of molecular regulators of carcinogenesis by studying gene expression during induction of cellular differentiation and quiescence in a three-dimensional (3D) cell culture model. Here, we report the discovery of a tumor suppressor gene located at chromosome 8p21.3-22 near marker D8S254. It is ubiquitously expressed in normal tissue and transiently up-regulated during initiation of cellular differentiation and quiescence in 3D cell culture. In contrast, mRNA expression was not detectable in tissue from pancreatic tumor and the pancreatic tumor cell line MIA PaCa-2. Recombinant expression in the tumor cell line MIA PaCa-2 inhibited proliferation, as shown by a 30% reduction of BrdU uptake after recombinant expression. Immunocytochemistry and Western blot analysis of subcellular fractions demonstrated a mitochondrial localization for the mature protein. In conclusion, we identified a tumor suppressor gene at chromosome 8p21.3-22, encoding a mitochondrial protein, controlling cellular proliferation.

Base Sequence↗