Osteoprotegerin as a predictor of renal and cardiovascular outcomes in renal transplant recipients: follow-up data from the ALERT study.

BACKGROUND: In patients with chronic kidney disease, vascular calcification contributes to increased cardiovascular (CV) morbidity and mortality. CV risk remains high after successful renal transplantation. Osteoprotegerin (OPG) is a glycoprotein, involved in the regulation of the vascular calcification process. Previous studies have shown that elevated OPG is predictive of mortality in high-risk populations. The aim of this study was to investigate the prognostic value of OPG for graft function, CV events and all-cause death, in a large transplant cohort. METHODS: OPG was measured at baseline in renal transplant recipients enrolled in the Assessment of Lescol in Renal Transplantation (ALERT) study, a randomized placebo-controlled intervention study comparing fluvastatin and placebo. Patients were followed for 6.7 years with evaluation of pre-specified end points, graft loss, graft function, CV events and death. RESULTS: OPG was analysed in 1889 renal transplant recipients, with a mean value of 4.69 ± 1.85 pg/L. The number of renal and CV events increased by quartiles of OPG. In the multivariate analysis, OPG in the fourth as compared to first quartile was an independent predictor of graft failure or doubling of serum creatinine [hazard ratio (HR) 2.20 (1.56-3.11), P < 0.001], major CV events [HR 2.40 (1.58-3.64), P < 0.001], cardiac mortality [HR 2.80 (1.32-5.94), P = 0.007] and all-cause mortality [HR 2.31 (1.53-3.49), P < 0.001]. CONCLUSION: In a large cohort of kidney transplant patients with long-term follow-up, OPG was independently associated with renal events, CV events and mortality.

Inflammation-associated graft loss in renal transplant recipients.

BACKGROUND: Although short-term graft survival has improved substantially in renal transplant recipients, long-term graft survival has not improved over the last decades. The lack of knowledge of specific causes and risk factors has hampered improvements in long-term allograft survival. There is an uncertainty if inflammation is associated with late graft loss. METHODS: We examined, in a large prospective trial, the inflammation markers high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) and their association with chronic graft dysfunction. We collected data from the Assessment of Lescol in Renal Transplant trial, which recruited 2102 maintenance renal transplant recipients. RESULTS: Baseline values were hsCRP 3.8 ± 6.7 mg/L and IL-6 2.9 ± 1.9 pg/mL. Adjusted for traditional risk factors, hsCRP and IL-6 were independently associated with death-censored graft loss, the composite end points graft loss or death and doubling of serum creatinine, graft loss or death. CONCLUSION: The inflammation markers hsCRP and IL-6 are associated with long-term graft outcomes in renal transplant recipients.

Asymmetrical dimethylarginine is associated with renal and cardiovascular outcomes and all-cause mortality in renal transplant recipients.

Increased plasma levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and predict the progression to dialysis and death in patients with chronic kidney disease. The effects of these increased ADMA levels in renal transplant recipients, however, are unknown. We used the data from ALERT, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin on cardiovascular and renal outcomes in 2102 renal transplant recipients with stable graft function on enrollment. Patients who were initially randomized to fluvastatin or placebo in the 5- to 6-year trial were offered open-label fluvastatin in a 2-year extension of the original study. After adjustment for baseline values for established factors in this post hoc analysis, ADMA was found to be a significant risk factor for graft failure or doubling of serum creatinine (hazard ratio 2.78), major cardiac events (hazard ratio 2.61), cerebrovascular events (hazard ratio 6.63), and all-cause mortality (hazard ratio 4.87). In this trial extension, the number of end points increased with increasing quartiles of plasma ADMA levels. All end points were significantly increased in the fourth compared to the first quartile. Our study shows that elevated plasma levels of ADMA are associated with increased morbidity, mortality, and the deterioration of graft function in renal transplant recipients.

hCMV induced IL-6 release in trophoblast and trophoblast like cells.

BACKGROUND: Human cytomegalovirus (hCMV) infection of the trophoblasts is a crucial event in virus transmission from mother to child, being one responsible factor for intrauterine infection of the unborn. Differences of virus replication in trophoblasts depending on time point of pregnancy and degree of differentiation of trophoblasts might influence this transmission. Furthermore, immunological reactions of the trophoblasts to hCMV infection might be important defence mechanisms too. OBJECTIVES: hCMV replication and interleukin-6 release in trophoblasts and trophoblast like cells (choriocarcinoma cells) was investigated. STUDY DESIGN: Trophoblasts from term and 1st trimester placentas were isolated and infected with hCMV. hCMV production and release to the supernatant as well as interleukin-6 release and interleukin-6 mRNA production by these infected cells was measured. Choriocarcinoma cell lines (JEG-3, JAR) were treated the same. Non-infected trophoblasts were used as controls. RESULTS: In 1st trimester trophoblast, term trophoblasts and JEG-3 permissive hCMV replication was observed, although with different kinetics and efficiency. In JAR no complete virus replication was seen. High levels of interleukin-6 were measured in the supernatants of all hCMV infected cells immediately after infection. IL-6 mRNA upregulation was seen 48 h after infection in those cell types replication of hCMV occurred (1st trimester trophoblasts, term trophoblasts, JEG-3). At that time-point hCMV immediate early proteins appeared. In JARs no virus production and no IL-6 mRNA upregulation was seen, and IL-6 levels in the supernatant of these hCMV infected cells declined significantly until day 6 after infection compared to mock infected cells. CONCLUSION: These observations show that hCMV replication is influenced by the degree of trophoblast differentiation. Interleukin-6 is upregulated by hCMV infection, but is independent of complete virus replication.

Adiponectin serum concentrations in men with coronary artery disease: the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study.

BACKGROUND: Adiponectin, the most abundant adipocytokine of adipose tissue cells, has recently been found to be decreased in coronary artery disease (CAD). Data concerning adiponectin in different stages of CAD are rare, and it was not investigated if adiponectin levels are influenced by the severity of angina pectoris. METHODS: Thus, we measured adiponectin serum levels by means of ELISA in 1626 male probands, including 273 control subjects, 367 subjects with silent CAD, 608 patients with stable, and 378 patients with unstable angina. RESULTS: As compared to controls (8.56; 5.85 to 12.85 microg/ml) and subjects with silent CAD (8.60; 5.99 to 12.64 microg/ml), adiponectin was significantly decreased in patients with stable (7.22; 5.06 to 10.41 microg/ml; p < 0.001 for both) and unstable angina (6.72; 4.08 to 10.08 microg/ml; p < 0.001 for both). By a logistic regression analysis, low adiponectin levels were identified as a significant independent predictor for stable and unstable angina (p < 0.001 for both). No significant differences of adiponectin were observed, neither between the stable and unstable angina group, nor between any classes of angina according to the Canadian Cardiovascular Society (CCS) Angina Score for stable angina. CONCLUSIONS: These results suggest, that decreased adiponectin levels are indicative for symptomatic CAD, but are not further influenced by the progression of this disease.

Early atherosclerosis in obese juveniles is associated with low serum levels of adiponectin.

CONTEXT: There is growing evidence that adiponectin, the most abundant adipocytokine of adipose tissue cells, plays a crucial role in advanced atherosclerosis. OBJECTIVE: The objective of the study was to evaluate the role of adiponectin in early atherosclerosis. DESIGN: One hundred forty obese juveniles (mean age, 13.5 +/- 4.4 yr) and 100 age-matched, healthy, normal-weight controls from the STYrian Juvenile Obesity Study were investigated. We measured adipocytokines, inflammatory biomarkers, parameters of insulin resistance, and lipid subfractions. Intima-media thickness (IMT) of common carotid arteries was determined by ultrasonography. Furthermore, lipometric measurements were performed in obese juveniles to determine the topographic distribution of sc adipose tissue (SAT). RESULTS: Compared with controls, the group of obese juveniles exhibited a significantly increased IMT (P < 0.001) and elevated high-sensitive C-reactive protein (P < 0.001), indicating early stages of atherosclerosis. Serum levels of adiponectin were highly significantly negatively correlated with carotid IMT, even after controlling for common cardiovascular risk factors (P < 0.001; r = -0.34). Furthermore, adiponectin was positively correlated with high-density lipoprotein-free cholesterol and serum apolipoprotein-A1 and negatively with triglycerides, insulin resistance, uric acid, and serum transaminases. By a multiple regression analysis, adiponectin was shown to be the strongest predictive variable for carotid IMT. Finally, adiponectin was found positively correlated with SAT thickness of the rear and inner thigh in boys and negatively with the SAT thickness of the neck in girls. CONCLUSION: In summary, our study describes an influence of SAT topography on adiponectin serum levels and provides first evidence that incipient atherosclerosis is associated with low serum levels of this adipocytokine.

Association of myeloperoxidase with total and cardiovascular mortality in individuals undergoing coronary angiography--the LURIC study.

BACKGROUND: The phagocytic enzyme myeloperoxidase (MPO) acts as a front-line defender against microorganisms. However, increased MPO levels have been found to be associated with complex and calcified atherosclerotic lesions and incident cardiovascular disease. Therefore, this study aimed to investigate a predictive role of MPO, a biomarker of inflammation and oxidative stress, for total and cardiovascular mortality in patients referred to coronary angiography. METHODS AND RESULTS: MPO plasma concentrations along with eight MPO polymorphisms were determined in 3036 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up 7.75 years). MPO concentrations were positively associated with age, diabetes, smoking, markers of systemic inflammation (interleukin-6, fibrinogen, C-reactive protein, serum amyloid A) and vascular damage (vascular cellular adhesion molecule-1 and intercellular adhesion molecule-1) but negatively associated with HDL-cholesterol and apolipoprotein A-I. After adjustment for cardiovascular risk factors MPO concentrations in the highest versus the lowest quartile were associated with a 1.34-fold risk (95% CI: 1.09-1.67) for total mortality. In the adjusted model the hazard ratio for cardiovascular mortality in the highest MPO quartile was 1.42 (95% CI: 1.07-1.88). Five MPO polymorphisms were positively associated with MPO concentrations but not with mortality. Using Mendelian randomization, we did not obtain evidence for a causal association of MPO with either total or cardiovascular mortality. CONCLUSIONS: MPO concentrations but not genetic variants at the MPO locus are independently associated with risk for total and cardiovascular mortality in coronary artery disease patients.

Cystatin C is independently associated with total and cardiovascular mortality in individuals undergoing coronary angiography. The Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

AIMS: Cystatin C is a well established marker of kidney function. There is evidence that cystatin C concentrations are also associated with mortality. The present analysis prospectively evaluated the associations of cystatin C with all-cause and cardiovascular (CV) mortality in a well-characterized cohort of persons undergoing angiography, but without overt renal insufficiency. METHODS: Cystatin C was available in 2998 persons (mean age: 62.7 ± 10.5 years; 30.3% women). Of those 2346 suffered from coronary artery disease (CAD) and 652 (controls) did not. Creatinine (mean ± SD: 83.1 ± 47.8 vs. 74.1 ± 24.7 µmol/L, p = 0.036) but not Cystatin C (mean ± SD: 1.02 ± 0.44 vs. 0.92 ± 0.26 mg/L, p = 0.065) was significantly higher in patients with CAD. After a median follow-up of 9.9 years, in total 898 (30%) deaths occurred, 554 (18.5%) due to CV disease and 326 (10.9%) due to non-CV causes. Multivariable-adjusted Cox analysis (adjusting for eGFR and established cardiovascular risk factors, lipid lowering therapy, angiographic coronary artery disease, and C-reactive protein) revealed that patients in the highest cystatin C quartile were at an increased risk for all-cause (hazard ratio (HR) 1.93, 95% CI 1.50-2.48) and CV mortality (HR 2.05 95% CI 1.48-2.84) compared to those in the lowest quartile. The addition of cystatin C to a model consisting of established cardiovascular risk factors increased the area under the receiver-operating characteristic curve for CV and all-cause mortality, but the difference was statistically not significant. However, reclassification analysis revealed significant improvement by addition of cystatin C for CV and all-cause mortality (p < 0.001), respectively. CONCLUSION: The concentration of cystatin C is strongly associated with long-term all-cause and cardiovascular mortality in patients referred to coronary angiography, irrespective of creatinine-based renal function.

Aldosterone/renin ratio determines peripheral and central blood pressure values over a broad range.

OBJECTIVES: With the present analysis we intended to investigate the magnitude of the effect of relative aldosterone excess in predicting peripheral as well as aortic blood pressure levels in a well-characterized cohort of patients undergoing coronary angiography. BACKGROUND: The discussion on the relationship between aldosterone concentration and blood pressure has recently gone beyond the role of primary aldosteronism in the genesis of arterial hypertension. METHODS: Plasma aldosterone (pg/ml) and plasma renin concentration (pg/ml) were determined in 3,056 Caucasian patients (age 62.5 +/- 11 years; 31.9% women) scheduled for coronary angiography in a single tertiary care center. We formed sex-specific deciles (D) according to plasma aldosterone/renin concentration ratio (ARR) (pg/ml/pg/ml). RESULTS: Mean peripheral systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the entire cohort were 141 +/- 24 mm Hg and 81 +/- 11 mm Hg, respectively. Mean ARR was 10.2 +/- 15.7 in men and 14.4 +/- 19.9 in women (p < 0.0001). Median SBP and aortic SBP increased steadily and significantly from ARR D1 (126.8 mm Hg and 130.0 mm Hg, respectively) to D10 (151.0 mm Hg and 149.6 mm Hg, respectively; p < 0.0001 for both) after multivariate adjustment for age, sex, body mass index, renal function, antihypertensive medications, and various parameters potentially influencing BP. Adjusted median DBP and aortic DBP also increased significantly from 74.3 mm Hg and 66.5 mm Hg (D1) to 86.9 mm Hg and 76.7 mm Hg, respectively (D10) (p < 0.001 for both). In a multivariate stepwise regression model, ARR emerged as the second most significant independent predictor (after age) of mean SBP and as the most important predictor of mean DBP in this patient cohort. CONCLUSIONS: Our results: 1) underline that the ARR affects BP well below a cutoff used for screening for primary aldosteronism; and 2) illustrate the importance of the ARR in modulating BP over a much wider range than is currently appreciated.

Determination of myeloperoxidase in EDTA plasma: comparison of an enzyme-linked immunosorbent assay with a chemiluminescent automated immunoassay.

BACKGROUND: The increased demand in clinical chemistry laboratories for determination of myeloperoxidase (MPO) as a potential marker for cardiovascular diseases has led to the development of several analytical methods, especially enzyme-linked immunosorbent assay (ELISA, e. g. from Immundiagnostik AG), and recently a new chemiluminescent automated immunoassay (CMIA, Architect MPO assay, Abbott Diagnostics). METHODS: We compared data from 115 patients obtained from an ELISA reference method (Immundiagnostik AG) with data obtained from the automated Architect MPO assay. RESULTS: The new MPO assay from Abbott Diagnostics correlates well with the ELISA (y=0.767x+7.035; R(2)=0.9204). The difference plot according to Bland-Altman analysis shows a mean bias of -1.048 microg/l, with a probability of 95%. CONCLUSIONS: The Architect MPO assay can easily be adapted to the Architect instrument system and it is advantageous as far as technology and analysis time are concerned. This new automated MPO assay shows excellent analytical performance and provides a precise and convenient automated method for the measurement of MPO.

Inflammation in renal transplantation.

BACKGROUND AND OBJECTIVES: Renal transplant recipients experience premature cardiovascular disease and death. The association of inflammation, all-cause mortality, and cardiovascular events in renal transplant recipients has not been examined in a large prospective controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin on cardiovascular and renal outcomes in 2102 renal transplant recipients. Patients initially randomized to fluvastatin or placebo in the 5- to 6-yr trial were offered open-label fluvastatin in a 2-yr extension to the original study. The association between inflammation markers, high-sensitivity C-reactive protein (hsCRP), and IL-6 on cardiovascular events and all-cause mortality was investigated. RESULTS: The baseline IL-6 value was 2.9 +/- 1.9 pg/ml (n = 1751) and that of hsCRP was 3.8 +/- 6.7 mg/L (n = 1910). After adjustment for baseline values for established risk factors, the hazard ratios for a major cardiac event and all-cause mortality for IL-6 were 1.08 [95% confidence interval (CI), 1.01 to 1.15, P = 0.018] and 1.11 (95% CI, 1.05 to 1.18, P < 0.001), respectively. The adjusted hazard ratio for hsCRP for a cardiovascular event was 1.10 (95% CI, 1.01 to 1.20, P = 0.027) and for all-cause mortality was 1.15 (95% CI, 1.06 to 1.1.25, P = 0.049). CONCLUSIONS: The inflammation markers IL-6 and hsCRP are independently associated with major cardiovascular events and all-cause mortality in renal transplant recipients.

Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality.

BACKGROUND: In cross-sectional studies, low serum levels of 25-hydroxyvitamin D are associated with higher prevalence of cardiovascular risk factors and disease. This study aimed to determine whether endogenous 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are related to all-cause and cardiovascular mortality. METHODS: Prospective cohort study of 3258 consecutive male and female patients (mean [SD] age, 62 [10] years) scheduled for coronary angiography at a single tertiary center. We formed quartiles according to 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels within each month of blood drawings. The main outcome measures were all-cause and cardiovascular deaths. RESULTS: During a median follow-up period of 7.7 years, 737 patients (22.6%) died, including 463 deaths from cardiovascular causes. Multivariate-adjusted hazard ratios (HRs) for patients in the lower two 25-hydroxyvitamin D quartiles (median, 7.6 and 13.3 ng/mL [to convert 25-hydroxyvitamin D levels to nanomoles per liter, multiply by 2.496]) were higher for all-cause mortality (HR, 2.08; 95% confidence interval [CI], 1.60-2.70; and HR, 1.53; 95% CI, 1.17-2.01; respectively) and for cardiovascular mortality (HR, 2.22; 95% CI, 1.57-3.13; and HR, 1.82; 95% CI, 1.29-2.58; respectively) compared with patients in the highest 25-hydroxyvitamin D quartile (median, 28.4 ng/mL). Similar results were obtained for patients in the lowest 1,25-dihydroxyvitamin D quartile. These effects were independent of coronary artery disease, physical activity level, Charlson Comorbidity Index, variables of mineral metabolism, and New York Heart Association functional class. Low 25-hydroxyvitamin D levels were significantly correlated with variables of inflammation (C-reactive protein and interleukin 6 levels), oxidative burden (serum phospholipid and glutathione levels), and cell adhesion (vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 levels). CONCLUSIONS: Low 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are independently associated with all-cause and cardiovascular mortality. A causal relationship has yet to be proved by intervention trials using vitamin D.

Implications of resistin plasma levels in subjects undergoing coronary angiography.

BACKGROUND: The adipokine resistin, which is thought to serve as a link between obesity and insulin resistance, was recently shown to exert proatherosclerotic features. OBJECTIVE: Our study aimed to explore the involvement of resistin in cardiovascular disease by investigating the associations of resistin with angiographic coronary artery disease (CAD), cardiovascular risk factors and mortality. DESIGN: The Ludwigshafen Risk and Cardiovascular Health (LURIC) study is a prospective study of white subjects who had undergone coronary angiography. PATIENTS AND MEASUREMENTS: Resistin levels were determined in 1162 subjects with (n = 911) and without (n = 251) angiographic CAD. During a mean follow-up period of 5.47 years, 198 deaths occurred among our probands. RESULTS: Resistin was positively correlated with C-reactive protein (CRP; r = 0.245, P < 0.001), vascular adhesion molecule-1 (VCAM-1; r = 0.327, P < 0.001) and intercellular adhesion molecule-1 (ICAM-1; r = 0.197, P < 0.001) and was negatively correlated with glomerular filtration rate (GFR; r = -0.438, P < 0.001) and high density lipoprotein (HDL; r = -0.196, P < 0.001). Multiple regression analysis revealed that GFR was the strongest predictive variable for resistin. Angiographic CAD, type 2 diabetes, smoking, hypertension and body mass index (BMI) were not associated with resistin. Compared to the first quartile, we observed an increased risk for cardiovascular and noncardiovascular mortality at the fourth quartile of resistin, but only the association between resistin and noncardiovascular mortality remained significant after multivariable adjustments [hazard ratio (HR) 4.92, 95% confidence interval (CI) 1.66-14.6, P = 0.004]. CONCLUSIONS: Resistin plasma concentrations are related to inflammatory processes and renal function but our study does not support the hypothesis of resistin as an independent cardiovascular risk factor. The unexpected association of resistin with noncardiovascular mortality still warrants further study.