Absence of Relationship Between Self-Reported Sleep Measures and Amyloid Load in Elderly Subjects.

Objective: To determine the relationships between self-reported sleep profile and cortical amyloid load in elderly subjects without dementia. Methods: This cross-sectional study included 143 community-dwelling participants aged ≥70 years (median: 73 years [70-85]; 87 females) with spontaneous memory complaints but dementia-free. Sociodemographic characteristics, health status, neuropsychological tests, sleep, and 18F-florbetapir (amyloid) PET data were collected. The clinical sleep interview evaluated nighttime sleep duration, but also daytime sleep duration, presence of naps, and restless leg syndrome (RLS) at time of study. Validated questionnaires assessed daytime sleepiness, insomnia, and risk of sleep apnea. The cortical standardized uptake value ratio (SUVr) was computed across six cortical regions. The relationship between sleep parameters and SUVr (cut-off ratio>1.17 and tertiles) was analyzed using logistic regression models. Results: Amyloid-PET was positive in 40.6% of participants. Almost 40% were at risk for apnea, 13.5% had RLS, 35.5% insomnia symptoms, 22.1% daytime sleepiness, and 18.8% took sleep drugs. No significant relationship was found between positive amyloid PET and nighttime sleep duration (as a continuous variable, or categorized into <6; 6-7; ≥7 h per night). Logistic regression models did not show any association between SUVr and daytime sleep duration, 24-h sleep duration, naps, RLS, daytime sleepiness, insomnia symptoms, and sleep apnea risk (before and after adjustment for APOEε4 and depressive symptoms). Conclusion: Our study did not confirm the association between amyloid-PET burden, poor sleep quantity/quality in elderly population, suggesting that the interplay between sleep, and amyloid is more complex than described.

Restless legs syndrome and iron deficiency in adults with attention-deficit/hyperactivity disorder.

STUDY OBJECTIVE: The association between restless legs syndrome (RLS), periodic leg movements during sleep (PLMS) and iron deficiency has been reported in children with attention-deficit/hyperactivity disorder (ADHD); however little is known in adults. The aim of this study was to assess frequencies of RLS, PLMS and other leg movements (LM) and iron deficiency and their relationships with ADHD phenotype in adults with ADHD. METHODS: Two hundred adults with ADHD (112 males, median age 31 years) were evaluated on lifetime ADHD symptoms and sleep characteristics. RLS was diagnosed according to standard criteria. Serum ferritin levels were measured, with iron deficiency defined as <50 ng/mL. A subgroup of 48 ADHD patients with RLS, 48 ADHD without RLS and 48 controls underwent a polysomnography to record sleep, LM, and PLMS. RESULTS: RLS was diagnosed in 33.0%, associated with earlier onset of ADHD, hyperactive presentation and more severe lifetime ADHD symptoms. Iron deficiency was found in 35.5% with higher frequency in patients with RLS. LM were more frequent in ADHD patients, with higher LM periodicity levels in those with comorbid RLS in comparison to controls. However, PLMS index did not differ between groups. Patients with ADHD and RLS had higher frequency of iron deficiency than other groups. CONCLUSIONS: In a large sample of adults with ADHD, we individualized a subgroup characterized by earlier and severe ADHD symptoms, RLS, higher LM during sleep and iron deficiency. This endophenotype may reflect a different neurobiological mechanism that remains to be further studied.

Heavy tobacco dependence in suicide attempters making recurrent and medically serious attempts.

AIMS: Tobacco dependence and suicidal behaviors have been repeatedly associated in several studies but their relationship is still unclear. We aim to investigate, specifically, the association between the level of tobacco dependence and the severity of suicidal outcomes among suicide attempters, as well as the relationship of impulsivity with both conditions. METHODS: We examined a cross-sectional sample of 542 adult suicide attempters to compare the characteristics of the attempts depending on the level of tobacco dependence, which was assessed with the Fagerstrom test. RESULTS: Smokers with heavy dependence (Fagerstrom ≥7) made more attempts and reached higher medical lethality compared to non-smokers. Smokers with moderate dependence were not associated with features of severity in the suicide attempts. The combination of high impulsivity and heavy tobacco dependence showed an additive effect on the number of suicide attempts. CONCLUSIONS: A high or very high level of tobacco dependence could indicate a specific vulnerability leading to more severe suicide attempts. Impulsive attempters with heavy tobacco dependence were particularly at risk.

Smoking, Alcohol, Drug Use, Abuse and Dependence in Narcolepsy and Idiopathic Hypersomnia: A Case-Control Study.

STUDY OBJECTIVES: Basic experiments support the impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Our aim was to assess the frequencies of smoking, alcohol and drug use, abuse and dependence in narcolepsy type 1 (NT1, hypocretin-deficient), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) (non-hypocretin-deficient conditions), in comparison to controls. We hypothesized that NT1 patients would be less vulnerable to drug abuse and addiction compared to other hypersomniac patients and controls from general population. METHODS: We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 450 adult patients (median age 35 years; 41.3% men) with NT1 (n = 243), NT2 (n = 116), IH (n = 91), and 710 adult controls. All participants were evaluated for alcohol consumption, smoking habits, and substance (alcohol and illicit drug) abuse and dependence diagnosis during the past year using the Mini International Neuropsychiatric Interview. RESULTS: An increased proportion of both tobacco and heavy tobacco smokers was found in NT1 compared to controls and other hypersomniacs, despite adjustments for potential confounders. We reported an increased regular and frequent alcohol drinking habit in NT1 versus controls but not compared to other hypersomniacs in adjusted models. In contrast, heavy drinkers were significantly reduced in NT1 versus controls but not compared to other hypersomniacs. The proportion of patients with excessive drug use (codeine, cocaine, and cannabis), substance dependence, or abuse was low in all subgroups, without significant differences between either hypersomnia disorder categories or compared with controls. CONCLUSIONS: We first described a low frequency of illicit drug use, dependence, or abuse in patients with central hypersomnia, whether Hcrt-deficient or not, and whether drug-free or medicated, in the same range as in controls. Conversely, heavy drinkers were rare in NT1 compared to controls but not to other hypersomniacs, without any change in alcohol dependence or abuse frequency. Although disruption of hypocretin signaling in rodents reduces drug-seeking behaviors, our results do not support that hypocretin deficiency constitutes a protective factor against the development of drug addiction in humans.

Osteoprotegerin and sclerostin in chronic kidney disease prior to dialysis: potential partners in vascular calcifications.

BACKGROUND: Osteoprotegerin (OPG), sclerostin and DKK1 constitute opposite bone turnover inhibitors, OPG inhibiting osteoclastogenesis while sclerostin and DKK1 exerting their inhibitory effects on osteoblastogenesis. Both proteins have been recognized as strong risk factors of vascular calcifications in non-dialysis chronic kidney disease (ND-CKD) patients. The aim of this study was to investigate the relationships between these inhibitors and coronary artery calcifications (CAC) in this population. METHODS: A total of 241 ND-CKD patients [143 males; 69.0 (25.0-95.0) years; median estimated glomerular filtration rate using CKD-EPI 35.1 (6.7-120.1) mL/min/1.73 m(2)] were enrolled in this cross-sectional study. All underwent chest multidetector computed tomography for CAC scoring. OPG, sclerostin, DKK1 and mineral metabolism markers including PTH and bone alkaline phosphatase were measured. Logistic regression analyses were used to study the relationships between CAC and these markers. RESULTS: Decline in renal function was associated with a significant increase in OPG and sclerostin while a slight but significant decrease in DKK1 was observed. The main crude associations with presence of CAC were a high level of OPG [OR = 2.55 95% confidence interval (95% CI) (1.35-4.82) for a level ranging from 6.26 to 9.15 pmol/L and OR = 5.74 95% CI (2.87-11.5) for a level ≥9.15 pmol/L; P < 0.0001] and a high level of sclerostin [OR = 2.64 95% CI (1.39-5.00) for a level ranging from 0.748 to 1.139 ng/mL and OR = 3.78 95% CI (1.96-7.31) for a level ≥1.139 ng/mL; P = 0.0002]. A logistic regression model clearly showed that the risk to present CAC was significantly increased when both OPG (≥6.26 pmol/L) and sclerostin (≥0.748 ng/mL) levels were high [crude model: OR = 11.47 95% CI (4.54-29.0); P < 0.0001; model adjusted for age, gender, diabetes, body mass index and smoking habits: OR = 5.69 95% CI (1.76-18.4); P = 0.02]. No association between DKK1 and presence of CAC was observed. CONCLUSIONS: Our results strongly suggest that bone turnover inhibitors, OPG and sclerostin, are independently associated with CAC with potential additive effects in ND-CKD patients.

Prevalence and smoking behavior characteristics of nonselected smokers with childhood and/or adult self-reported ADHD symptoms in a smoking-cessation program: a cross-sectional study.

BACKGROUND: ADHD involves impairing core symptoms of inattention and hyperactivity/impulsivity in children (childhood ADHD = CH) that may persist in adulthood (adult ADHD = AD). Conflicting findings have been found regarding AD prevalences among adult smokers, and it is unclear whether AD is associated with a more severe smoking behavior in adulthood. OBJECTIVE: The aim of this article is (a) to determine CH and AD prevalences in a nonselected sample of adult smokers, (b) to describe the characteristics of smokers with ADHD symptoms versus those without, and (c) to determine whether CH and/or AD symptoms are risk factors for more severe smoking in adulthood. METHOD: Three hundred and seventy-three participants aged 18 years and over were prospectively recruited in a smoking-cessation unit. Participants were classified as "no ADHD symptoms," "CH symptoms," or "AD symptoms" according to their baseline score on the Wender Utah Rating Scale (WURS) alone (for CH symptoms) and WURS combined to the Adult Self Report Scale (ASRS) for AD symptoms. Other clinical variables were reported at first consultation. RESULTS: (a) CH symptoms were reported in 15.3% (57/373) of the total sample, 42.1% (24/57) of whom also had persistent ADHD symptoms in adulthood (prevalence of AD was 24/373 = 6.4%). (b) In comparison with participants without ADHD symptoms, smokers with ADHD symptoms consume significantly more tobacco, but ADHD symptoms were no longer significantly associated with the daily number of smoked cigarettes after adjustment for sociodemographic variables. No significant association was found between the two groups and age at the first cigarette, age at onset daily smoking, and nicotine dependence. (c) Participants were categorized into three groups: Group 1 without ADHD symptoms lifetime (NH; n = 316), Group 2 with childhood history of ADHD symptoms (CH; n = 33), and Group 3 with Adult ADHD symptoms (AD; n = 24). The association with tobacco consumption (>20 cigarettes/day) was significant for CH only (p = .02). After adjustment for gender, age, professional status, and educational level, this association was not longer significant. CONCLUSION: Childhood and adult ADHD symptoms are both highly prevalent among nonselected smokers but our study failed to show more severe smoking characteristics among these participants after adjustment with sociodemographic variables.

Impact of axis-I comorbidity and suicidal behavior disorders on sensitivity and specificity of the Mood Disorder Questionnaire in complex depressed inpatients.

OBJECTIVE: This study assessed the psychometric performance of the Mood Disorder Questionnaire (MDQ) and its modified MDQ7 version, to screen for bipolar disorders (BD) in depressive inpatients according to depression severity, number of current axis I psychiatric comorbidities and suicidal behavior disorders. METHODS: Depressed adult inpatients (n=195) were consecutively enrolled. Psychiatric diagnoses were made using the standardized DSM-IV-TR structured interview MINI 5.0.0 and medical case notes. Depression severity was assessed with the Beck Depression Inventory and the Hamilton Depression Scale. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each MDQ version were evaluated in the whole sample and according to depression severity, current axis I psychiatric comorbidities and suicidal behavior. RESULTS: The occurrence and the number of axis I disorders affected performance of both versions. Among depressed patients with two or more comorbidities, PPV and NPV of the MDQ were 65% and 80%, respectively, and they were respectively 56.2% and 87.9% with MDQ7. Current suicidal behavior disorders also dramatically reduced the PPV of MDQ (from 81.2% to 63.3%) and MDQ7 (from 72.2% to 52.6%) but the NPV remained above 80%. The performance of both versions of the MDQ tended to improve with the severity of depression. CONCLUSION: The MDQ is not a suitable screening instrument to diagnose BD in subjects with a complex major depressive episode and/or a current history of suicidal behavior. Nevertheless MDQ particularly in its modified version may be useful for ruling out the presence of BD among these complex patients.

Hypnotics and mortality in an elderly general population: a 12-year prospective study.

BACKGROUND: Hypnotics are widely used by the elderly, and their impact on mortality remains controversial. The inconsistent findings could be due to methodological limitations, notably the lack of control for underlying sleep symptoms or illness associated with hypnotic use, for example, insomnia symptoms and excessive daytime sleepiness, depression and anxiety. Our objective was to examine the association between the use of hypnotics and mortality risk in a large cohort of community-dwelling elderly, taking into account a wide range of potential competing risks including sociodemographic characteristics, lifestyle, and chronic disorders as well as underlying psychiatric disorders and sleep complaints. METHODS: Analyses were carried out on 6,696 participants aged 65 years or older randomly recruited from three French cities and free of dementia at baseline. Adjusted Cox proportional hazards models with delayed entry, and age of the participants as the time scale, were used to determine the association between hypnotic use and 12-year survival. RESULTS: At baseline, 21.7% of the participants regularly used at least one hypnotic. During follow-up, 1,307 persons died, 480 from cancer and 344 from cardiovascular disease. Analyses adjusted for study center, age and gender showed a significantly greater risk of all-cause and cardiovascular-related mortality with hypnotics, particularly benzodiazepines, and this increased with the number of hypnotics used. None of these associations were significant in models adjusting for sociodemographic and lifestyle characteristics, chronic disorders including cardiovascular pathologies, sleep and psychiatric disorders. Results remained unchanged when duration of past hypnotic intake or persistent versus intermittent use during follow-up were taken into account. CONCLUSIONS: When controlling for a large range of potential confounders, the risk of mortality was not significantly associated with hypnotic use regardless of the type and duration. Underlying psychiatric disorders appear to be the principal confounders of the observed association.

Homocysteine as a determinant of left ventricular ejection fraction in patients with diabetes.

BACKGROUND: A link between homocysteine (Hcy) and left ventricular ejection fraction (LVEF) emerged from recent studies but was yet not explored specifically in diabetic patients. This study aimed to assess the relationship between LVEF and Hcy in a cohort of adults with diabetes. METHODS: LVEF was determined through the measure of left ventricular end-diastolic/end-systolic volumes in 409 consecutive asymptomatic patients with diabetes who underwent stress myocardial perfusion imaging. Clinical and biological parameters which were determinants of LVEF in univariate analyses with p<0.15 were included in a multivariate analysis. RESULTS: In univariate analyses, factors significantly associated with a LVEF<55% were gender [women vs. men, odds ratio (OR)=0.22 (0.13; 0.38)], peripheral arterial disease [OR=2.49 (1.34; 4.62)], active smoking [OR=1.97 (1.16; 3.33)], silent myocardial ischemia (SMI) [OR=2.19 (1.25; 3.86)], the highest vs. the lowest tertile of creatinine [OR=2.08 (1.17; 3.68)], of albuminuria [OR=2.22 (1.27; 3.90)] and of Hcy [OR=1.83 (1.07; 3.13)]. No relationship was observed between blood pressure and decrease in LVEF. In the multivariate analysis, female gender was confirmed as being protective for having a LVEF<55%. Presence of SMI [OR=2.20 (1.14; 4.23)] and Hcy ≥15 µmol/L [OR=1.81 (1.06; 3.07)] were the two remaining significant factors associated with an increased relative risk of having LVEF<55%. A trend was only observed for the criteria active smokers. CONCLUSIONS: This study highlights an inverse relationship between Hcy and LVEF in patients with diabetes, independent of age, gender, SMI, smoking, blood pressure, renal function, folates, vitamin B12, lipid parameters and hepatic enzymes.

Bone biomarkers help grading severity of coronary calcifications in non dialysis chronic kidney disease patients.

BACKGROUND: Osteoprotegerin (OPG) and fibroblast growth factor-23 (FGF23) are recognized as strong risk factors of vascular calcifications in non dialysis chronic kidney disease (ND-CKD) patients. The aim of this study was to investigate the relationships between FGF23, OPG, and coronary artery calcifications (CAC) in this population and to attempt identification of the most powerful biomarker of CAC: FGF23? OPG? METHODOLOGY/PRINCIPAL FINDINGS: 195 ND-CKD patients (112 males/83 females, 70.8 [27.4-94.6] years) were enrolled in this cross-sectional study. All underwent chest multidetector computed tomography for CAC scoring. Vascular risk markers including FGF23 and OPG were measured. Logistic regression analyses were used to study the potential relationships between CAC and these markers. The fully adjusted-univariate analysis clearly showed high OPG (≥10.71 pmol/L) as the only variable significantly associated with moderate CAC ([100-400[) (OR = 2.73 [1.03;7.26]; p = 0.04). Such association failed to persist for CAC scoring higher than 400. Indeed, severe CAC was only associated with high phosphate fractional excretion (FEPO(4)) (≥38.71%) (OR = 5.47 [1.76;17.0]; p = 0.003) and high FGF23 (≥173.30 RU/mL) (OR = 5.40 [1.91;15.3]; p = 0.002). In addition, the risk to present severe CAC when FGF23 level was high was not significantly different when OPG was normal or high. Conversely, the risk to present moderate CAC when OPG level was high was not significantly different when FGF23 was normal or high. CONCLUSIONS: Our results strongly suggest that OPG is associated to moderate CAC while FGF23 rather represents a biomarker of severe CAC in ND-CKD patients.

Does hemodiafiltration improve the removal of homocysteine?

High prevalence of hyperhomocysteinemia is common in hemodialysis (HD) patients and could contribute to worsen the cardiovascular risk. Beyond vitamin B status, dialysis modality itself could influence homocysteine (Hcy) levels. The objective was compare the reduction rate (RR) of Hcy and cysteine in stable dialyzed patients treated by standard HD or hemodiafiltration (HDF). Seventy-five patients undergoing stable dialysis through standard high-flux HD (n = 35) or HDF (n = 40) were included. Biological parameters were determined before and after a midweek dialysis session. Urea percent reduction per session and Kt/V index (K, body urea clearance, T, time of dialysis, and V, urea distribution volume), defined as a marker of dialysis efficacy, were similar between HD and HDF groups. By contrast, higher RR of beta2 microglobulin (ß2m) was observed in HDF compared with HD (78.6 vs. 72.0%, respectively; P < 0.001). Likewise, higher RR of Hcy was obtained with HDF compared to HD (46.0 vs. 41.5%, respectively; P < 0.05), whereas the RR of cysteine was similar in both groups. Interestingly, a positive correlation between Hcy RR and urea Kt/V index was observed (r = 0.29, P < 0.05) and between Hcy RR and ß2m RR (r = 0.45, P < 0.001). Time-averaged concentration (TAC) of Hcy was lower with HDF compared with HD (17.8 vs. 19.1 µmol/L, respectively), although not significant. There was no difference in median Hcy according to dialysis modality for neither pre- nor postdialysis levels. Significant higher removal of Hcy was observed with HDF compared with standard HD, although urea Kt/V index was similar. Enhanced removal of middle molecules, such as ß2m, could be involved in Hcy RR improvement with HDF.

Biocompatibility of heparin-grafted hemodialysis membranes: impact on monocyte chemoattractant protein-1 circulating level and oxidative status.

This prospective observational study aimed at evaluating efficacy and biocompatibility performances of the new heparin-coated Evodial dialyzers with/without systemic heparin reduction. After a 4-week wash-out period with reference polysulfone F70S dialyzers, 6 hemodialysis patients were sequentially dialyzed with Evodial, F70S, and Evodial dialyzers using 30% heparin reduction, each period of treatment was 4 weeks. Removal rates (RR) (urea, creatinine, and ß2-microglobulin), dialysis dose, and instantaneous clearances (urea and creatinine) were measured as well as inflammatory (C-reactive protein, fibrinogen, interleukin 6, tumor necrosis factor α, and monocyte chemoattractant protein-1) and oxidative stress (OS) (superoxide anion, homocysteine, and isoprostanes) parameters at the end of each study period. Patients treated with Evodial or F70S dialyzers for 4 weeks presented comparable dialysis efficacy parameters including urea and creatinine RR, dialysis dose and instantaneous clearances. By contrast, a significantly lower but reasonably good ß2-microglobulin RR was achieved with Evodial dialyzers. Regarding biocompatibility, no significant difference was observed with inflammation and OS except for postdialysis monocyte chemoattractant protein-1 which significantly decreased with Evodial dialyzers. Thirty percent heparinization reduction with Evodial dialyzers did not induce any change in inflammation but led to an improvement in OS as demonstrated by a decrease in postdialysis superoxide production and predialysis homocysteine and isoprostane. This bioactive dialyzer together with heparin dose reduction represents a good trade-off between efficacy and biocompatibility performance (improvement in OS with a weak decrease in efficacy) and its use is encouraging for hemodialysis patients not only in reducing OS but also in improving patient comorbid conditions due to lesser heparin side effects.

Higher psychological pain during a major depressive episode may be a factor of vulnerability to suicidal ideation and act.

BACKGROUND: It has been suggested that psychological pain ("psychache") is a key factor in the suicidal process. In addition, suicidal acts may be best understood within a stress-vulnerability model. We hypothesized that more intense psychache during a major depressive episode would be a factor of vulnerability to suicidal behavior. METHODS: Patients hospitalized for a major depressive episode, including 87 individuals with a recent history of suicidal acts, 61 individuals with a past history of suicidal acts, and 62 individuals without any suicidal history, were assessed at admission using several Visual Analog scales to measure levels of psychache, physical pain and suicidal ideation. RESULTS: Patients with a recent or past history of suicide attempts expressed significantly higher levels of current psychological pain, and a higher intensity and frequency of current suicidal ideation than patients without any history of suicidal acts. The level of current psychache was significantly and positively associated with intensity and frequency of suicidal ideation. There were no between-group differences for physical pain. LIMITATIONS: Medication status was not controlled. A lack of statistical power may have masked an association between physical pain and suicidal ideation. CONCLUSIONS: Higher psychological pain during a major depressive episode may be a factor of vulnerability to suicidal behavior, by increasing the propensity to suicidal ideation. Measuring and taking care of psychache during a depressive episode should be a major therapeutic target during crisis intervention.

A cut-off value of plasma osteoprotegerin level may predict the presence of coronary artery calcifications in chronic kidney disease patients.

BACKGROUND: Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Osteoprotegerin (OPG) could play a key role in bone-vascular calcification imbalance and could be a marker of vascular calcification extent and progression. The purpose of this study was to evaluate relationships between vascular risk biomarkers (including classic risk factors and OPG) and coronary artery calcification (CAC) extent in chronic kidney disease (CKD) patients and to establish within the markers the appropriate cut-off value to predict CAC. METHODS: A total of 133 non-dialyzed CKD patients at various stages of kidney disease [75 males/58 females, median age: 69.9 (27.4-94.6)] were enrolled, excluding extrarenal replacement therapy patients. All underwent chest multidetector computed tomography for CAC scoring. Blood samples were collected for measurement of vascular risk markers (kidney disease, inflammation, nutrition, calcium phosphate and OPG). A potential relationship between CAC and these biological markers was investigated, and a receiver-operating characteristic (ROC) curve was designed thereafter to identify a cut-off value of involved markers that best predicted the presence of CAC. RESULTS: After adjustment for age, diabetes, smoking and gender, among biological markers, only low-estimated glomerular filtration rate using Modification of Diet in Renal Disease [OR = 3.63 (1.10-12.02)], high FEPO(4) [OR = 3.99 (1.17-13.6)] and high OPG levels [OR = 8.54 (2.14-34.11)] were associated with the presence of CAC. A protective effect of 1.25(OH)(2) vitamin D [OR = 0.20 (0.05-0.79)] and LDL cholesterol [OR = 0.27 (0.08-0.94)] on CAC was also observed. ROC curve analysis showed that the OPG best cut-off value predicting CAC was 757.7 pg/mL. CONCLUSION: These results suggest that a CAC increase is strongly associated with a plasma OPG increase in CKD patients. The values of OPG >757.7 pg/mL allow us to predict the presence of CAC in these patients.

Fine-tuning of the prediction of mortality in hemodialysis patients by use of cytokine proteomic determination.

BACKGROUND AND OBJECTIVES: Inflammation-induced atherosclerosis and enhanced susceptibility to infection are linked to immune dysfunction and account for an important part of mortality in hemodialysis patients. This 4-yr prospective study aimed to use cytokine proteomic determination for predicting cardiovascular and noncardiovascular mortality in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Levels of 12 cytokines were measured using a proteomic biochip system in 134 patients who were on stable hemodialysis and compared with a control group of 150 healthy volunteers. Cox proportional hazards regression analysis was used to determine the relationship between cytokine and clinical outcome. RESULTS: A proinflammatory state characterized by decreased anti-/proinflammatory cytokine ratio was evidenced in hemodialysis patients compared with control subjects. After adjustment for age, gender, smoking, and high-sensitivity C-reactive protein levels, IL-6 and (IL-4+IL-10)/IL-6 ratio were associated with a significant and specific enhanced hazard ratio of cardiovascular mortality (hazard ratio 11.32 [95% confidence interval 2.52 to 50.90; P < 0.01] and hazard ratio 3.14 [95% confidence interval 1.20 to 8.22; P < 0.05], respectively, when comparing the third and first tertiles). It is interesting that (IL-4+IL-6+IL-10)/(IL-2+IFN-gamma) ratio, used as a marker of lymphocytes T helper subsets cytokine secretion, was associated only with noncardiovascular mortality (hazard ratio 4.93; 95% confidence interval 1.03 to 23.65; P < 0.05). CONCLUSION: Beyond the strong prediction of cardiovascular mortality by IL-6, determination of cytokine ratios can be useful to identify hemodialysis patients with increased noncardiovascular mortality risk.

Creatinine index and transthyretin as additive predictors of mortality in haemodialysis patients.

BACKGROUND: Malnutrition and inflammation are recognized as important predictors of poor clinical outcome in haemodialysis (HD). This study was designed to estimate the relative contribution of known biological markers of inflammation, malnutrition and muscle mass in the prognosis of HD patients. METHODS: A total of 187 HD patients (100 women, 87 men, median age 66.7 years [22.3-93.5]) were followed-up yearly for 5 years. At baseline, pre-dialysis values of C-reactive protein (CRP), albumin, transthyretin, total HDL- and LDL-cholesterol and triacylglycerol were determined. Estimation of creatinine index (CI) as muscle mass marker was determined by creatinine kinetic modelling using pre- and post-dialysis creatinine values. RESULTS: During the follow-up period, 89 deaths (53 from cardiovascular causes) were observed. After adjustment for age, gender, dialysis vintage, smoking, diabetes mellitus and hypertension, the highest tertile of CRP and lowest tertile of transthyretin and CI were significantly associated with all-cause mortality (relative risk (RR)=1.98 [1.12-3.47], 2.58 [1.48-4.50], 2.71 [1.42-5.19], respectively). In addition, low CI had an additive value to low levels of transthyretin. In contrast, high cholesterol (RR=0.47 [0.27-0.83], P=0.0091) and vitamin E concentrations (RR=0.46 [0.26-0.80], P= 0.006) showed a protective trend for all-cause mortality. In the multivariate analysis, transthyretin appeared as the most predictive biological marker of non-CV mortality (RR=3.78 [1.30-10.96], P=0.014), and CI of CV mortality (RR=2.61 [1.06-6.46], P=0.038), respectively. Discussion. These results confirm that uraemic malnutrition constitutes an important risk factor for mortality in HD. Beyond transthyretin, CI seems to be an additional marker routinely available and monthly determined in HD patients.

Association of aminothiols with the clinical outcome in hemodialysis patients: comparison of chromatography and immunoassay for homocysteine determination.

BACKGROUND: Controversial results on hyperhomocysteinemia and cardiovascular risk in hemodialysis (HD) could be due in part to the methodology used for homocysteine (Hcy) determination. OBJECTIVE: The aim of this study was to compare the influence of the method used for Hcy determination (chromatography or immunoassay) with regard to the association of Hcy with cardiovascular mortality rate in HD patients in a 3-year prospective study. METHODS: A total of 162 patients undergoing HD were included in a cohort study. Baseline Hcy levels were measured by HPLC and fluorescence polarization immunoassay (FPIA). Cysteine and cysteinylglycine were determined simultaneously with Hcy measurement by HPLC. RESULTS: Hcy levels obtained with both methods were highly correlated (r(2)=0.927, p<0.0001). An increased relative risk (RR) for cardiovascular mortality (n=31) was found between the highest against lowest tertile of Hcy for both HPLC (RR 2.74, 95% CI 1.07-7.02; p<0.05) and FPIA (RR 2.76, 95% CI 0.99-7.70; p=0.05). Interestingly, increased cysteine (> or =452 micromol/L) and cysteinylglycine (> or =36.6 micromol/L) levels were associated with a decreased RR of non-cardiovascular death (n=26) (RR 0.27, 95% CI 0.09-0.79; p=0.02) for cysteine and (RR 0.28, 95% CI 0.09-0.90; p=0.03) for cysteinylglycine when compared to the first tertile. CONCLUSIONS: This study demonstrated an increased risk of cardiovascular mortality in HD patients with Hcy values in the third tertile, independent of the method used. HPLC offers the advantage of simultaneous determination of other aminothiols that appear to be associated with non-cardiovascular mortality.

Plasma osteoprotegerin is associated with mortality in hemodialysis patients.

Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Regulating molecules such as osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) could play a key role in bone-vascular calcification imbalance. This study investigated the contribution of these proteins as well as mineral metabolism disorders in hemodialysis (HD) patient outcome. A total of 185 HD patients were followed up prospectively for 2 yr. In addition to clinical characteristics, mineral metabolism markers as well as OPG and soluble RANKL (sRANKL) were measured at baseline. After 2 yr, survival rates were described with Kaplan-Meier and compared with Cox regression analyses; 50 patients died (27 from cardiovascular diseases). Calcium, phosphate, and calcium x phosphate product were not associated with mortality. Both hyperparathyroidism (parathyroid hormone > or =300 pg/ml) and hypoparathyroidism (parathyroid hormone <150 pg/ml) were poorly associated with all-cause and cardiovascular mortality. By contrast, elevated OPG levels predicted all-cause (relative risk [RR] 2.67; 95% confidence interval [CI] 1.32 to 5.41; P = 0.006) and cardiovascular mortality (RR 3.15; 95% CI 1.14 to 8.69; P = 0.03). Low levels of sRANKL were associated with a protective effect for all-cause mortality (RR 0.45; 95% CI 0.21 to 0.94; P = 0.03). The association of OPG with all-cause mortality was stronger in patients with C-reactive protein > or =12.52 mg/L. In this condition, both highest (RR 5.68; 95% CI 1.48 to 22.73; P = 0.01) and lowest tertiles (RR 5.37; 95% CI 147 to 1968; P = 0.01) significantly predicted poor outcome. These results show that regulating-bone molecules, especially OPG, are strong predictors of mortality in HD patients, suggesting that OPG is a vascular risk factor, in particular in patients who have high C-reactive protein levels. OPG determination therefore should be added to the biologic follow-up of these patients.

Association between novel indices of malnutrition-inflammation complex syndrome and cardiovascular disease in hemodialysis patients.

BACKGROUND: Inflammation and malnutrition are recognized as important risk factors for cardiovascular disease (CVD) in hemodialysis (HD) patients. Owing to substantial short-term variability of serum C-reactive protein (CRP), more reliable markers of malnutrition-inflammation complex syndrome should be sought with stronger associations with the risk of CVD in HD patients. We therefore explored the clinical relevance of a composite inflammatory index (prognostic inflammatory and nutritional index [PINI]) and of muscle protein mass indicators, derived from creatinine kinetics. METHODS: This cross-sectional study included 177 HD patients (89 women and 88 men; median age, 67.73 years). CVD and risk factors were assessed using medical charts, clinical examination, and biochemical measurements performed at inclusion. Lean body mass (LBM) was derived from creatinine kinetic modeling, whereas PINI was calculated as the ratio (CRP xalpha1-acid-glycoprotein)/(albumin x transthyretin). Patients were divided according to the presence or absence of established CVD. RESULTS: The traditional risk factors diabetes (odds ratio [OR], 5.83; p = 0.0045) and smoking (OR, 3.50; p < 0.02) were associated with an increase in prevalent CVD. Low transthyretin (OR, 3.79; p < 0.02) and high levels of CRP (OR, 2.70; p < 0.05), PINI (OR, 3.44; p < 0.02), observed LBM (OR, 3.01; p < 0.05), and the ratio of observed/expected LBM (OR, 4.24; p < 0.01) were associated with CVD after adjustment for age, sex, dialysis center, and dialysis vintage. After additional adjustment for diabetes and smoking, only PINI (OR, 2.85; p = 0.0446) and observed/expected LBM (OR, 2.96; p = 0.0361) were still significant. CONCLUSION: PINI and LBM are associated with increased relative risk for having CVD and could be used routinely to examine the degree of severity of malnutrition inflammation complex syndrome.