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Biomedical subjects

Christoph Wanner

Publications and source records attributed to Christoph Wanner.

67 records · Page 4Linked to original sources
PubMed2002

L-arginine deficiency and supplementation in experimental acute renal failure and in human kidney transplantation.

BACKGROUND: The "L-arginine paradox" refers to situations where L-arginine (L-Arg) supplementation stimulates nitric oxide (NO) synthesis, despite saturating intracellular concentrations. This paradox is frequently observed in acute renal failure (ARF). First, the effects of L-Arg on renal function of rats with ARF were studied. Based on the promising results from these initial studies, the second part of our study searched for a form of ARF in humans that could be studied easily under conditions with little variance and yet was linked with endothelial dysfunction. Thus, we investigated the effects of L-Arg supplementation immediately after kidney transplantation in 54 patients. METHODS: In uranyl nitrate-induced ARF in rats the effects of L-Arg and L-NNA (inhibitor of nitric oxide synthase; NOS) on glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure (BP) and NOx (NO2- +NO3-) excretion were examined. Tissue L-Arg levels, NOS activities, immunodetection of NOS and superoxide dismutase (SOD), activities of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine oxidase, and nitrotyrosine immunoreactive protein (NT-IR) were determined and compared to sham operated animals. Secondly, in a randomized, double-blind study, the effects of L-Arg on GFR and RPF were investigated in 54 kidney transplant recipients, receiving IV L-Arg for three days. GFR and RPF were measured on days 1, 3, 5 and 10 by scintigraphy. RESULTS: In experimental ARF, decreased RPF and GFR were associated with reduced tissue L-Arg levels, endothelial NOS-III expression, NO formation and NOx excretion. Reduction in GFR, RPF and NOx excretion were reversed upon administration of exogenous L-Arg. There also was a loss of Cu,Zn-SOD, a key enzyme against oxidative stress, and an elevation of NT-IR, an indicator of nitrosative stress and suggested marker for pathological actions of NO. However, NT-IR was not dependent on de novo NO synthesis and not related to the functional effects of l-Arg administration. In kidney transplant recipients receiving organs with a short cold ischemia time (CIT) and from young donors, that is, those with a higher likelihood of a functional endothelium, early administration of L-Arg improved renal function. CONCLUSION: Both experimental and clinical data show that \L-Arg deficiency and endothelial dysfunction are pathomechanistically relevant in ARF. The data suggest a therapeutic potential for the administration of L-Arg in ARF and kidney transplantation, at least in patients receiving kidneys with shorter CIT and from younger donors.

Acute Kidney Injury↗
PubMed2002

Advanced glycation end products and mortality in hemodialysis patients.

BACKGROUND: Advanced glycation and oxidation end products (AGEs) cause oxidative stress and trigger cytokine driven inflammatory reactions in vitro. The net effects on markers of inflammation and acute phase proteins in vivo as well as their influence on survival in hemodialysis patients are unknown. METHODS: We conducted a cross-sectional study in 312 stable hemodialysis patients and analyzed the interrelationships of AGEs and C-reactive protein (CRP) and their predictive effect on all-cause as well as cardiovascular mortality. Mortality was monitored prospectively over a period of 32 months. AGEs were determined by measuring total serum fluorescent AGEs (AGE-fl) and Nepsilon-(carboxymethyl)-lysine (CML). RESULTS: The levels of AGE-fl, CML and CRP were 3.2-, 3.8- and 10-fold higher as compared to healthy controls. AGE-fl and CML levels correlated significantly with each other but not with CRP or serum albumin. Patients with high (above median values) AGE-fl or CML levels (109 x 103 AU and 1.4 microg/mL, respectively) had a significant better survival than those with low (below median values) AGE-fl or CML levels. Patients with high CRP levels (above 7.7 mg/L = median value) had a better survival than those with low CRP (below median value) when AGE-fl or CML levels were high in parallel. CONCLUSIONS: In contrast to in vitro data and to current hypotheses, the presence of high serum AGEs, as measured by AGE-fl and CML, were not linked to increased mortality. Statistically, high serum AGEs partly overcame the negative impact of the acute phase response on mortality in hemodialysis patients. Whether the benefit of high serum AGEs is an epiphenomenon or reflects a better nutritional support needs further studies.

Adult↗
PubMed2002

Inflammation and outcome in end-stage renal failure: does female gender constitute a survival advantage?

BACKGROUND: Elevated C-reactive protein (CRP) is a strong predictor of cardiovascular events and all-cause mortality in end-stage renal disease (ESRD) patients. However, although sex hormones may influence serum levels of inflammatory proteins, gender has not been taken into consideration in previous studies of inflammation and outcome in ESRD patients. METHODS: We included 663 (374 males) ESRD patients (59 +/- 1 year) from three European renal centers (Sweden, Germany and Italy) in which CRP levels and outcome data (follow-up 33 +/- 1 months) were available. The relation between outcome and serum levels of the soluble intercellular adhesion molecule (sICAM-1) was evaluated in 312 of the patients. RESULTS: The present study shows that elevated CRP is a strong predictor of outcome, but whereas no difference in all-cause mortality was observed between non-inflamed (CRP <or=3.4 mg/L) males and females, inflamed males had a significantly (log rank 6.1; P = 0.01) higher mortality rate than inflamed females. A strong positive correlation between CRP and sICAM-1 was found in the combined patient material (rho = 0.37; P < 0.0001) as well as in the male (rho = 0.25; P < 0.01) and female (rho = 0.52; P < 0.0001) subgroups. The Cox proportional hazard model showed that whereas both elevated sICAM-1 and log CRP predicted outcome in males, neither predicted outcome significantly in females. CONCLUSIONS: As inflamed female patients have a better outcome that inflamed males the present observation suggests that sex hormones may have important cardioprotective effects that limit the effect of inflammation on vascular injury in female ESRD patients.

Age Distribution↗
PubMed2002

Inflammation and cardiovascular risk in dialysis patients.

BACKGROUND: Chronic inflammation, as evidenced by increased levels of C-reactive protein (CRP), predicts all-cause and cardiovascular mortality in hemodialysis patients in short-term studies. Whether CRP is also predictive in the long-term follow-up is unknown. METHODS: We conducted a 4-year follow-up of a cross-sectional study in a cohort of 280 stable hemodialysis patients. CRP was determined once at the beginning of the study, and all-cause as well as cardiovascular mortality was monitored prospectively. RESULTS: During follow-up, 123 patients (43.9%) had died, mostly from cardiovascular events (58.5%) corresponding to an annual mortality rate of 11%. Overall mortality and cardiovascular mortality were significantly higher in patients with a CRP more than 8 mg/L (73% vs. 39% and 87% vs. 55%, respectively). Multivariate Cox regression analysis demonstrated that age, CRP, and preexisting cardiovascular disease were the most powerful predictors, but the presence of diabetes, albumin, and BMI also remained in the model. CONCLUSION: A single determination of CRP is a powerful indicator of all cause and cardiovascular death even after a follow-up period of 4 years in patients on hemodialysis treatment.

Acute-Phase Reaction↗
PubMed2002

The metabolic burden of diabetes and dyslipidaemia in chronic kidney disease.

Hyperglycaemia induces mitochondrial superoxide production, increases oxidative stress, and leads to activation of the acute-phase response. Hyperglycaemia, impaired renal function, and uraemia cause inflammatory and oxidative processes. Advanced oxidation protein products and advanced glycation end products are formed, leading to subsequent cytokine release. This promotes alterations in lipoprotein metabolism, composition, and function. These changes result in a highly atherogenic environment, perpetuating the vicious cycle of accelerated atherogenesis. The terminal pathway is an elevation of C-reactive protein, a biomarker of both overall and cardiovascular outcome.

Diabetes Mellitus↗
PubMed2002

C-reactive protein a marker for all-cause and cardiovascular mortality in haemodialysis patients.

Inflammation is thought to play a central role in the aetiology and outcome of atherosclerosis. C-reactive protein (CRP) is a prominent product of the inflammatory response syndrome and a marker of overall and cardiovascular death in the general population and in dialysis patients. CRP is 5- to 10-fold higher in haemodialysis patients than in healthy controls and clearly is multifactorial in origin. A number of endogenous factors have been identified in vitro [angiotensin II, lipopolysacharide, modified low-density lipoprotein (LDL), advanced glycation end-products, homocysteine, viral infections] which all are able to trigger a nuclear factor (NF)-kappaB-mediated inflammatory, interleukin-6-driven, response via the generation of oxygen free radicals (oxidative stress). In addition, exogenous factors (dialysate endotoxin, vascular access, cuprophane dialyser material) have been identified in clinical studies which are also responsible, at least in part, for high serum CRP levels. Some of these factors function by themselves as non-traditional cardiovascular risk factors. Whether CRP is simply a marker of cardiovascular disease and mortality or whether it is in the causal pathway of the disease remains an open question. Recent data are in favour of a direct involvement in the pathogenesis of disease, since binding of CRP to degraded LDL enhances complement activation and induces the expression of tissue factor.

Biomarkers↗
PubMed2002

Novel insights into uremic vascular calcification: role of matrix Gla protein and alpha-2-Heremans Schmid glycoprotein/fetuin.

Cardiovascular mortality is markedly increased in the dialysis population when compared to non-uremic subjects. Vascular and valvular calcifications are most frequently found in dialysis patients at risk and are independent predictors of cardiovascular death in this population. Traditionally, the presence of hyperphosphatemia and an increased calcium x phosphate product was considered a major pathomechanistic condition leading to excessive vascular and soft-tissue calcifications in uremic subjects. Recent studies in knockout mice, however, revealed that deficiencies in calcium-regulatory proteins may also directly contribute to the development of extraosseus calcifications. alpha(2)-Heremans Schmid glycoprotein and matrix Gla protein are important inhibitors of calcification in vivo and there is novel evidence available that a deficiency in such proteins is involved in the pathogenesis of cardiovascular calcifications in dialysis patients.

Animals↗
PubMed2002

Uremia-specific alterations in lipid metabolism.

Uremic patients suffer from a secondary form of complex dyslipidemia consisting of quantitative and qualitative abnormalities in serum lipoproteins resulting in altered lipoprotein composition and metabolism. The most prominent are an increase in serum triglyceride levels (due to elevated very-low-density lipoprotein remnants and intermediate-density lipoprotein) and low high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein (LDL) cholesterol is often normal, but the cholesterol may originate from the atherogenic small and dense LDL subclass. The apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide modification of the enzymatic and advanced glycation end-product, oxidation or glycosylation). Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote prolonged circulation. HDL particles are structurally altered during states of inflammation. The contribution of this complex and atherogenic form of dyslipidemia to cardiovascular disease in patients with renal disease is at present unclear. Most studies are negative in demonstrating the predictive power of serum lipids for the development of cardiovascular disease. This is most likely due to interference with deteriorating aspects of the activated acute-phase response. Since it is also still unclear whether we have therapeutics available with a sufficient impact on LDL size, remnant lipoprotein lowering and restoration of HDL function, we urgently need specific intervention trials.

Coronary Artery Disease↗
PubMed2001

Oxidized LDL suppresses NF-kappaB and overcomes protection from apoptosis in activated endothelial cells.

Atherosclerosis is a chronic inflammatory disease associated with enhanced apoptotic cell death in vascular cells, partly induced by oxidized low-density lipoprotein (OxLDL). However, proinflammatory stimuli such as lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) activate endothelial cells (EC) and inhibit apoptosis through induction of nuclear factor kappaB (NF-kappaB)-dependent genes. This study therefore investigated whether OxLDL or its component, lysophosphatidylcholine (LPC), interacts with the effect of LPS or TNF-alpha on cell survival. Human EC were incubated with LPS, TNF-alpha, OxLDL, or LPC alone or in combinations. OxLDL (100 to 200 microg/ml) and LPC (100 to 300 microM) induced apoptosis dose-dependently. LPS and TNF-alpha had no effect on cell survival in the presence or absence of OxLDL or LPC. LPS and TNF-alpha both induced the antiapoptotic gene A20, whereas OxLDL and LPC suppressed its induction. Expression of A20 is regulated by NF-kappaB. OxLDL and LPC dose-dependently suppressed NF-kappaB activity. For functional analysis, bovine EC were transfected with A20 encoding expression constructs in sense and antisense orientation. Bovine EC that overexpressed A20 were protected against OxLDL-induced apoptosis, whereas expression of antisense A20 rendered cells more sensitive to OxLDL. These results suggest that OxLDL not only induces cell death, as has been shown before, but also compromises antiapoptotic protection of activated EC. OxLDL sensitizes EC to apoptotic triggers by interfering with the induction of A20 during the inflammatory response seen in atherosclerotic lesions. This inhibition is based on repression of NF-kappaB activation. The effect may be caused by the OxLDL component LPC.

Animals↗
PubMed2000

Stimulation of NADPH oxidase by oxidized low-density lipoprotein induces proliferation of human vascular endothelial cells.

Oxidized low-density lipoprotein (OxLDL) exerts proliferation and apoptosis in vascular cells, depending on its concentration and the duration of exposure. Recent studies indicate that [O(2)](-) is involved in cell cycle regulation and that OxLDL stimulates endothelial cells to produce [O(2)](-). This study examined the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as a potential source for [O(2)](-) in the proliferation-inducing activity of OxLDL in cultured human umbilical vein endothelial cells (HUVEC). Human LDL was oxidized by Cu(++), and proliferation of HUVEC was detected by 3H-thymidine incorporation. OxLDL (5 microg/ml) caused an increase in proliferation of HUVEC of 250 to 300%. OxLDL-induced proliferation was blocked by addition of the antioxidants superoxide dismutase and catalase, suggesting that enhanced [O(2)](-) formation was involved. Diphenylene iodonium (DPI, 1 microM), an inhibitor of NADPH oxidase, also prevented OxLDL-induced proliferation of HUVEC, indicating that NADPH oxidase was the source for enhanced [O(2)](-) formation. The OxLDL effect was mimicked by lysophosphatidylcholine (LPC, 10 microM), a compound formed during oxidation of LDL. LPC-induced proliferation was also prevented by coincubation with DPI. Treatment of HUVEC with [O(2)](-) generated by the xanthine/xanthine oxidase reaction resulted in proliferation as did treatment with OxLDL. As expected, this stimulation could not be blocked by DPI. With the use of the cytochrome c-assay, it was demonstrated that OxLDL and LPC enhanced [O(2)](-) formation in HUVEC (by factor 3.2 and by factor 3.5, respectively). Supporting the assumption that NADPH oxidase was the enzyme responsible for [O(2)](-) formation, cells transfected with antisense oligonucleotides for NADPH oxidase showed a significantly reduced [O(2)](-) formation after stimulation with OxLDL and LPC. OxLDL and its compound LPC induce proliferation of HUVEC through activation of NADPH oxidase. The active NADPH oxidase generates [O(2)](-), which mediates the proliferative effects.

Catalase↗