👤 A Lingenhel

Comparative proteomics identified the vitamin E-binding plasma protein afamin as a potential novel tumor marker for ovarian cancer. In addition, we observed in a previous small study decreased plasma concentrations of apolipoprotein A-IV (apoA-IV) in preoperative patients with kidney cancer. The aim of this study was therefore to analyze afamin and apoA-IV in a large case-control study to evaluate the diagnostic utility of the two potential novel tumor markers in ovarian cancer patients. We measured plasma concentrations of afamin and apoA-IV by means of a specific sandwich-type ELISA using affinity-purified polyclonal and monoclonal antibodies in 181 ovarian cancer patients of various clinical stages, 399 patients with benign gynecologic diseases, including endometriosis, and 177 controls and compared results with those for the conventional ovarian cancer tumor marker cancer antigen 125 (CA125). Afamin concentrations decreased from a median of 70.7 mg/L (range, 34.6-116.1 mg/L) in healthy controls to 65.2 mg/L (range, 20.2-206.6 mg/L) in patients with benign gynecologic diseases to 56.0 mg/L (range, 4.7-96.0 mg/L) in ovarian cancer patients (P < 0.001 for all pairwise comparisons). Similar results were obtained with apoA-IV concentrations decreasing from 13.0 mg/dL (range, 5.5-34.0 mg/dL) in controls to 11.7 mg/dL (range, 2.0-32.3 mg/dL) in benign conditions to 9.4 mg/dL (range, 0.3-29.5 mg/dL) in ovarian cancer (all P < 0.001). Receiver operating characteristic analysis for differentiating ovarian cancer patients from healthy controls revealed for a specificity of 90% sensitivity values of 92.4%, 42.4%, and 40.8% for CA125, afamin, and apoA-IV, respectively. Afamin, but not apoA-IV, added independent diagnostic information to CA125 and age for differentiating ovarian cancer from benign and healthy samples; the odds ratio of ovarian cancer was reduced by 44% for each doubling of afamin (P = 0.032). The relatively low sensitivity, however, clearly indicates that afamin and apoA-IV alone are not sufficiently suitable as diagnostic markers for ovarian cancer. Afamin contributes, however, independent diagnostic information to CA125, thus establishing its potential as an adjunct marker to CA125. Show less

ApoA-IV, an apolipoprotein (apo) with antioxidant, antiatherogenic, and antiinflammatory properties, was recently demonstrated to inhibit dextran sulfate sodium (DSS)-induced experimental colitis in mice. We therefore hypothesized that apoA-IV may be associated with disease activity in patients with inflammatory bowel disease (IBD). We addressed this question by testing for associations between apoA-IV genotypes, apoA-IV plasma levels, inflammatory parameters, and clinical disease activity in 206 patients with Crohn's disease (CD), 95 subjects with ulcerative colitis (UC), and 157 healthy controls. In CD patients, apoA-IV plasma levels were inversely associated with C-reactive protein (CRP) (P = 0.005) and disease activity (P = 0.01) in univariate analysis. In multiple logistic regression analysis, apoA-IV levels were identified as an independent predictor of elevated CRP (odds ratio [OR] 0.956, 95% confidence interval [CI]: 0.916-0.998, P = 0.04) and active disease (OR 0.957, 95% CI: 0.918-0.998, P = 0.04). In UC patients the apoA-IV gene variant 360 His (P = 0.03) but not apoA-IV levels (P = 0.15) were associated with increased disease activity in univariate analysis. This association, however, was lost in multiple logistic regression analysis (OR 3.435, 95% CI 0.995-11.853, P = 0.05). To our knowledge, this is the first study to demonstrate an association of apoA-IV with disease activity in patients with CD. Further studies are needed to define the relationship of apoA-IV to IBD. Show less

Increased plasma concentrations of apolipoprotein A-IV (apoA-IV) in chronic renal disease suggest a metabolic role of the kidney for this antiatherogenic protein. Therefore, we investigated patients with various forms of proteinuria and found increased serum concentrations of apoA-IV in 124 nephrotic patients compared with 274 controls (mean 21.9 +/- 9.6 vs. 14.4 +/- 4.0 mg/dl; P < 0.001). Decreasing creatinine clearance showed a strong association with increasing apoA-IV levels. However, serum albumin levels significantly modulated apoA-IV levels in patients with low creatinine clearance, resulting in lower levels of apoA-IV in patients with low compared with high albumin levels (21.4 +/- 8.6 vs. 29.2 +/- 8.4 mg/dl; P = 0.0007). Furthermore, we investigated urinary apoA-IV levels in an additional 66 patients with a wide variety of proteinuria and 30 controls. Especially patients with a tubular type of proteinuria had significantly higher amounts of apoA-IV in urine than those with a pure glomerular type of proteinuria and controls (median 45, 14, and 0.6 ng/mg creatinine, respectively). We confirmed these results in affected members of a family with Dent's disease, who are characterized by an inherited protein reabsorption defect of the proximal tubular system. In summary, our data demonstrate that the increase of apoA-IV caused by renal impairment is significantly modulated by low levels of serum albumin as a measure for the severity of the nephrotic syndrome. From this investigation of apoA-IV in urine as well as earlier immunohistochemical studies, we conclude that apoA-IV is filtered through the normal glomerulus and is subsequently reabsorbed mainly by proximal tubular cells. Show less

Apolipoprotein A-IV (ApoA-IV) is a 46 kD glycoprotein thought to protect against atherosclerosis. It is synthesized primarily in epithelial cells of the small intestine. Elevated plasma concentrations of ApoA-IV in patients with chronic kidney disease suggest that the human kidney is involved in ApoA-IV metabolism. To investigate whether the human kidney directly metabolizes ApoA-IV and which kidney tissue compartment is involved therein, ApoA-IV was localized by immunohistochemistry in 28 healthy kidney tissue samples obtained from patients undergoing nephrectomy. ApoA-IV mRNA expression was analyzed by real-time polymerase chain reaction (PCR) to exclude de novo synthesis in the kidney. ApoA-IV immunostaining was detected in proximal and distal tubular cells, capillaries and blood vessels but not inside glomeruli. ApoA-IV was predominantly found in the brush border of proximal tubules and in intracellular granules and various plasma membrane domains of both proximal and distal tubules. mRNA expression analysis revealed that no ApoA-IV was produced in the kidney. The immunoreactivity of ApoA-IV observed in kidney tubular cells suggests a direct role of the human kidney in ApoA-IV metabolism. The granular staining pattern probably represents lysosomes degrading ApoA-IV. The additional ApoA-IV localization in distal tubules suggests a rescue function to reabsorb otherwise escaping ApoA-IV in case proximal tubules cannot reabsorb all ApoA-IV. Since no mRNA expression could be detected in any kidney cells, the observed ApoA-IV immunoreactivity represents uptake and not de novo synthesis of ApoA-IV. Show less

Apolipoprotein (apo) A-IV is an antiatherogenic apolipoprotein, which may be involved in the regulation of food intake. Plasma apoA-IV is elevated in human obesity and apoA-IV polymorphisms have been associated with the extent of obesity. Our aim was to determine the effects of weight loss on plasma apo-IV in obese adolescents and to examine the relation of apoA-IV with the degree of obesity. Longitudinal intervention study of a low fat hypocaloric diet conducted in a dietary camp. Two groups of obese adolescents (n=47 and n=29), age: 12.7+/-1.7 and 11.7+/-2.6 y, relative body mass index (RBMI): 168+/-24 and 175+/-34%, respectively. Plasma total apoA-IV, apoA-I, apoB, plasma distribution of apoA-IV, leptin, lipids, and lipoproteins before and after 3 weeks of weight reduction. Plasma apoA-IV decreased from 11.5+/-4.1 mg/dl before to 6.7+/-2.2 mg/dl after weight reduction in the first group (P<0.001) and to a similar extent in the second group. The relative amount of lipid-free apoA-IV and apoA-IV associated with apoA-I increased slightly, whereas apoA-IV associated with lipoproteins devoid of apoA-I decreased. ApoA-IV levels before and after weight reduction and the changes in plasma apoA-IV did not independently correlate with RBMI, weight loss, or plasma leptin. Plasma apoA-IV decreases markedly in overweight adolescents undergoing short-term weight reduction. The decrease is not directly related to the degree of weight loss and the mechanisms underlying this reduction remain to be clarified. Show less

Recent studies showed lower apolipoprotein A-IV (apoA-IV) plasma concentrations in patients with coronary artery disease (CAD). The actual distribution of the antiatherogenic apoA-IV in human plasma, however, is discussed controversially and it was never investigated in CAD patients. We therefore developed a gentle technique to separate the various apoA-IV-containing plasma fractions. Using a combination of precipitation of all lipoproteins with 40% phosphotungstic acid and 4 M MgCl2, as well as immunoprecipitation of all apoA-I-containing particles with an anti-apoA-I antibody, we obtained three fractions of apoA-IV: lipid-free apoA-IV (about 4% of total apoA-IV), apoA-IV associated with apoA-I (LpA-I:A-IV, 12%), and apoA-I-unbound but lipoprotein-containing apoA-IV (LpA-IV, 84%). We compared these three apoA-IV fractions between 52 patients with a history of CAD and 52 age- and sex-matched healthy controls. Patients had significantly lower apoA-IV levels when compared to controls (10.28 +/- 3.67 mg/dl vs. 11.85 +/- 2.82 mg/dl, P = 0.029), but no major differences for the three plasma apoA-IV fractions. We conclude that our gentle separation method reveals a different distribution of apoA-IV than in many earlier studies. No major differences exist in the apoA-IV plasma distribution pattern between CAD patients and controls. Therefore, the antiatherogenic effect of apoA-IV has to be explained by other functional properties of apoA-IV (e.g., the antioxidative characteristics). Show less

Dyslipidemic factors obviously contribute to the high cardiovascular risk in dialysis patients but are often an underestimated problem. Therefore, we determined the prevalence of dyslipidemic factors in a large group of unselected hemodialysis (N = 564) and CAPD (N = 168) patients. We used the recently published recommendations of the Medical Experts Group concerning cardiovascular risk factors for the categorization of dyslipidemic factors. These were total cholesterol>200 mg/dL, low-density lipoprotein (LDL) cholesterol>100 mg/dL, high-density lipoprotein (HDL) cholesterol <40 mg/dL, triglycerides>180 mg/dL, and Lp(a)>30 mg/dL. CAPD patients had, in sum, a markedly worse lipid profile when compared with HD patients. They had higher frequencies of elevated total cholesterol (67% vs. 34%), triglycerides (47% vs. 28%), and Lp(a) concentrations (37% vs. 30%) when compared with HD patients. In both patient groups, about two thirds of the patients had LDL cholesterol above 100 mg/dL and HDL cholesterol below 40 mg/dL. When we analyzed the total frequency of dyslipidemic factors, we observed that the CAPD group included a markedly higher number of patients with three or four concurrent dyslipidemic factors than HD patients (P < 0.001). Furthermore, we analyzed apolipoprotein A-IV (apoA-IV), which was recently shown to be associated with cardiovascular disease, and which was about twice as high in both patient groups when compared with controls (P < 0.001). Dyslipidemic risk factors are highly prevalent in dialysis patients, and the concomitant occurrence of several risk factors in a given patient is more often observed in CAPD than HD patients. Show less