Lipid profiling of lipoprotein X: Implications for dyslipidemia in cholestasis.

Lipoprotein X (Lp-X) is an abnormal lipoprotein that may typically be formed in intra- and extrahepatic cholestasis and potentially interfere with lipid analysis in the routine lab. To gain insight into lipid class and species composition, Lp-X, LDL and HDL from cholestatic and control serum samples were subjected to mass spectrometric analysis including phospholipids (PL), sphingolipids, free cholesterol (FC), cholesteryl esters (CE) and bile acids. Our analysis of Lp-X revealed a content of 46% FC, 49% PL with 34% phosphatidylcholine (PC) as main PL component. The lipid species pattern of Lp-X showed remarkable high fractions of mono-unsaturated species including PC 32:1 and PC 34:1 and phosphatidylethanolamine (PE) 32:1 and 34:1. LDL and HDL lipid composition in the same specimens strongly reflected the lipid composition of Lp-X with increased PC 32:1, PC 34:1, PE 32:1, PE 34:1 and FC accompanied by decreased CE compared to controls. Comparison of Lp-X and biliary lipid composition clearly indicates that Lp-X does not originate from a sole release of bile lipids. Moreover, these data present evidence for increased hepatic fatty acid and PL synthesis which may represent a reaction to high hepatic FC level observed during cholestasis.

Influence of cytokine gene polymorphisms on erythropoetin dose requirements in chronic haemodialysis patients.

BACKGROUND: Chronic inflammation influences renal anaemia and reduce erythropoetin effectiveness. Chronic kidney disease and haemodialysis (HD) induce elevated cytokine and C-reactive protein (CRP) levels at an inter-individually variable extent. These differences are in part due to polymorphisms within cytokine genes, e.g. for pro-inflammatory interleukin-6 (IL-6) and anti-inflammatory interleukin-10 (IL-10). We hypothesized that these polymorphisms influence erythropoetin effectiveness. METHODS: Genotyping for polymorphisms of IL-6 (-174G/C) and IL-10 (-1082G/A) genes was done in 460 prevalent HD patients. Erythropoetin requirements were determined after three months of stable dosing of erythropoesis stimulating proteins (ESP). The effect of the cytokine genotypes was evaluated by multiple regression analysis. RESULTS: The presence of the IL-6 -174G allele (found to be related with higher secretion of IL-6) was associated with a 26% higher ESP dose compared with individuals without the G allele (P = 0.008). The IL-10 -1082 G/A polymorphism was not associated with ESP needs. Multivariate analysis detected a predictive value for ESP dose of the IL-6 polymorphism (P = 0.022), the haemoglobin level and the dose of i.v. iron, but not of age, gender, dialysis vintage, ferritin or the CRP value. CONCLUSIONS: Presence of the IL-6 allele -174G is related to higher ESP doses in chronic HD patients. The polymorphism of the anti-inflammatory IL-10 does not influence ESP dose, probably due to the fact that this cytokine has directly inhibitory effects on haematopoiesis in addition to its beneficial effects on inflammation.

Enhanced flow velocity after stenting of renal arteries is associated with decreased renal function.

BACKGROUND: Atherosclerotic renal artery stenosis (RAS) is frequently treated by angioplasty and stent placement. Duplex sonography is an established noninvasive technique for patient follow-up. There is lack of evidence that routine monitoring of asymptomatic patients with stable blood pressure is needed. METHODS: Renal duplex sonography was performed in 64 patients who had received percutaneous angioplasty and stenting of an atherosclerotic RAS. Duplex sonographic diagnosis was made by a combination of direct flow measurement in the renal artery and evaluation of intrarenal resistive indices. Renal function was determined by serum creatinine and calculated glomerular filtration rate (GFR). RESULTS: With a mean follow-up of 28 months after angioplasty, a flow velocity of >2.0 m/s was detected within the stented arteries in 11/64 patients. While the initial blood pressure and GFR as well as the influence of angioplasty on these parameters were not different, the decrease in renal function over time was significantly higher in patients with flow enhancement (annual GFR decrease, 8.0 ml/min vs. 0.8 ml/min; p < 0.05). CONCLUSION: Follow-up duplex sonography in patients after renal artery stenting detected an unexpectedly high rate of in-stent restenosis associated with enhanced loss of renal function. Routine duplex sonographic follow-up may detect patients at risk of more rapidly declining renal function.

Event-related potentials in people at risk for vascular dementia.

This study examined the relationship between the integrity of cerebrovascular microcirculation, neuropsychological testing and event-related potential indices of cognitive functioning in a nonclinical group of participants being at risk for vascular dementia. Sonographic measures, magnetic resonance (MR) scans and ERPs were recorded in 30 participants treated for arterial hypertension, with no report of neurological or psychiatric disorders. As a sonographic measure of cerebral microcirculation, the arteriorvenous cerebral transit time (cTT) was recorded. While neuropsychological measures of memory functions and general mental ability functions did not show systematic correlations with the cTT and other measures of vascular pathology, a pronounced correlation was obtained between P3a latency and cTT. Participants with long cTT showed a delayed P3a. These findings suggest that the P3a is a sensitive measure for reduced cognitive functions even at early stages of cerebrovascular pathology and by this may be a valuable tool for the early identification of cognitive deficits in individuals being at risk for vascular dementia.

Risk of occupational human herpesvirus 8 infection for health care workers.

Human herpesvirus 8 (HHV-8), or Kaposi's sarcoma-associated herpesvirus, is highly prevalent in certain risk groups (human immunodeficiency virus-infected patients, transplant recipients, and patients on hemodialysis). Heath care workers caring for these patients were found to be more frequently infected with HHV-8 than staff caring for other patients (P < 0.01).

Uremia-associated immune defect: the IL-10-CRP axis.

Unstable atherosclerotic disease is related to systemic inflammation. While this inflammation remains at a subclinical level in otherwise healthy individuals, chronic elevation of pro-inflammatory cytokines is a common feature in patients with end-stage renal disease (ESRD). Current hypotheses on the pathogenetic links between inflammation and atherosclerosis emphasize that cytokine-producing monocytes/macrophages can actively infiltrate atherosclerotic plaques. A high activation level of this cell type may contribute to plaque growth. In the healthy, some 15% to 20% of circulating monocytes may be activated for cytokine production. This percentage is much higher in dialysis patients (50%), which may contribute to the rapid progression of atherosclerosis. Anti-inflammatory mechanisms such as interleukin-10 (IL-10) limit the production of a broad range of pro-inflammatory factors. Animal models, as well as clinical findings, suggest an involvement of this cytokine in the pathogenesis of vascular lesions. In hemodialysis (HD) patients, a protective role of IL-10 against systemic inflammation could be proven. A high interindividual variability in IL-10 production leads to distinct patient groups who can or cannot effectively limit the uremia- and dialysis-induced inflammation. Single nucleotide polymorphisms (SNPs) in the promotor of the IL-10 gene may genetically explain this heterogeneity. The IL-10 genotype strongly influences the range of variation of C-reactive protein (CRP), the most widely used marker of inflammation in dialysis patients. By limiting the inflammatory activation in ESRD patients, the IL-10 genotype is predictive for the risk of cardiovascular disease, meaning that the IL-10 "high-producer" genotype is associated with a lower event rate, and even mortality, than the IL-10 "low-producer" genotype.

Anti-inflammatory interleukin-10 genotype protects dialysis patients from cardiovascular events.

BACKGROUND: Inflammatory processes play an important role for the progression of atherosclerosis. This can be studied particularly well in patients with chronic renal failure who are on hemodialysis, as they show systemic inflammation due to uremia and dialysis while suffering from premature mortality secondary to rapidly progressing atherosclerosis. Interleukin (IL)-10 is a regulatory cytokine that limits inflammatory processes. The quantitative production of IL-10 is subject to genetic variation based on polymorphisms in the promoter of its gene. We tested the hypothesis that the IL-10 genotype, by influencing the capacity to compensate for dialysis-induced systemic inflammation, determines the risk for cardiovascular complications. METHODS: Three hundred chronic hemodialysis patients were genotyped for the polymorphic bases at positions -1082 and -819 of the IL-10 promoter sequence. They were prospectively followed for a mean of 20.2 +/- 7.3 months. End-points of the study were major events related to cardiac, cerebrovascular or peripheral artery disease. RESULTS: The -1082A* allele, which is associated with low production of the cytokine IL-10 and elevated markers of systemic inflammation such as C reactive protein, was predictive for a higher cardiovascular morbidity (relative risk for cardiovascular events 2.76, 95% confidence interval 1.31 to 4.17, P = 0.004) compared to the -1082G* genotype. CONCLUSION: The IL-10 genotype influences the risk for cardiovascular events in hemodialysis patients and allows the definition of a high risk group. The data provide further evidence for a causal role of systemic inflammation for progressive atherosclerosis in dialysis patients.