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Objective: Insomnia complaints are frequent among kidney transplant (kTx) recipients and are associated with fatigue, depression, lower quality of life and increased morbidity. However, it is not known if subjective insomnia symptoms are associated with objective parameters of sleep architecture. Thus, we analyze the association between sleep macrostructure and EEG activity versus insomnia symptoms among kTx recipients. Methods: Participants (n1 = 100) were selected from prevalent adult transplant recipients (n0 = 1214) followed at a single institution. Insomnia symptoms were assessed by the Athens Insomnia Scale (AIS) and standard overnight polysomnography was performed. In a subgroup of patients (n2 = 56) sleep microstructure was also analyzed with power spectral analysis. Results: In univariable analysis AIS score was not associated with sleep macrostructure parameters (sleep latency, total sleep time, slow wave sleep, wake after sleep onset), nor with NREM and REM beta or delta activity in sleep microstructure. In multivariable analysis after controlling for covariables AIS score was independently associated with the proportion of slow wave sleep (β = 0.263; CI: 0.026–0.500) and REM beta activity (β = 0.323; CI = 0.041–0.606) (p < 0.05 for both associations). Conclusions: Among kTx recipients the severity of insomnia symptoms is independently associated with higher proportion of slow wave sleep and increased beta activity during REM sleep but not with other parameters sleep architecture. The results suggest a potential compensatory sleep protective mechanism and a sign of REM sleep instability associated with insomnia symptoms among this population.

Leptin is a hormone made by adipocytes and associated with hypertension, inflammation, and coronary artery disease. Low serum leptin level was associated with higher risk of death in patients with advanced chronic kidney disease. Little is known about the association of serum leptin with outcomes in kidney transplant recipients.Prospective prevalent cohort.We collected sociodemographic and clinical parameters, medical and transplant history, and laboratory data of 979 prevalent kidney transplant recipients. Associations between serum leptin level and death with a functioning graft, all-cause death, and death-censored graft loss over a 6-year follow-up period were examined in survival models.Serum leptin levels showed moderate negative correlation with eGFR (R = -0.21, P .001) and positive correlations with BMI (R = 0.48, P .001) and C-reactive protein (R = 0.20, P .001). Each 10 ng/mL higher serum leptin level was associated with 7% lower risk of death with functioning graft (hazard ratio [HR] (95% confidence interval [CI]), 0.93 (0.87-0.99)), and this association persisted after adjustment for confounders: HR (95% CI), 0.90 (0.82-0.99). Similar associations were found with all-cause death as outcome. The association between serum leptin level and risk of graft loss was nonlinear, and only low serum leptin level was associated with higher risk of graft loss.In prevalent kidney transplant recipients, lower serum leptin was an independent predictor of death.

Study objectives Periodic limb movements in sleep (PLMS) are frequent motor phenomena; however, population-based data are scarce. We assessed the prevalence of PLMS and factors associated with PLMS within two German population-based cohorts, the SHIP-TREND and BiDirect. Methods Single-night polysomnography was performed on 1107 subjects recruited from the general population (mean age: 52.9 years, 54.1% men) in the SHIP-TREND and on 247 participants (mean age: 57.6 years, 50.6% men) in the BiDirect. PLMS were evaluated using the standard criteria of the American Academy of Sleep Medicine. Sociodemographic data, behavioral variables, medical history, current medication, and other sleep disorders were assessed. Results The prevalence of PLMS index (PLMSI) >15/hour was 32.4% (SHIP-TREND) and 36.4% (BiDirect). In multivariable models, age (odds ratio [OR] = 1.05 per +1 year), male gender (OR = 2.20), restless legs syndrome (OR = 2.32), physical inactivity (OR = 1.52), current smoking (OR = 1.49), diabetes (OR = 2.13), antidepressant use (OR = 2.27), lower serum magnesium (OR per -0.1 mmol/L = 1.27) showed a positive, and the intake of beta-blockers an inverse association with PLMSI >15/hour in SHIP-TREND. In BiDirect, age (OR = 1.13 per +1 year), body mass index (OR = 1.11 per +1 kg/m2), and restless legs syndrome (OR = 8.77) were significantly associated with PLMSI >15/hour. Conclusions A high PLMSI is frequent in the German population. Age, male gender, restless legs syndrome, physical inactivity, current smoking, obesity, diabetes, antidepressant use, and lower magnesium were independently associated with PLMSI >15/hour in at least one of the cohorts.

Resistin is an adipocytokine that is associated with inflammation, coronary artery disease, and other types of cardiovascular disease among patients with normal kidney function. However, little is known about the association of resistin with outcomes in kidney transplant recipients. We collected socio-demographic and clinical parameters, medical and transplant history, and laboratory data from 988 prevalent kidney transplant recipients enrolled in the Malnutrition-Inflammation in Transplant-Hungary Study (MINIT-HU study). Serum resistin levels were measured at baseline. Associations between serum resistin level and death with a functioning graft over a 6-year follow-up period were examined in unadjusted and adjusted models. The mean±SD age of the study population was 51 ± 13 years, among whom 57% were men and 21% were diabetics. Median serum resistin concentrations were significantly higher in patients who died with a functioning graft as compared to those who did not die during the follow-up period (median [IQR]: 22[15-26] vs. 19[14-22] ng/ml, respectively; P < 0.001). Higher serum resistin level was associated with higher mortality risk in both unadjusted and fully adjusted models: HRs (95% CI): 1.33(1.16-1.54) and 1.21(1.01-1.46), respectively. In prevalent kidney transplant recipients, serum resistin was an independent predictor of death with a functioning graft.

Objectives Popular belief holds that the lunar cycle affects human physiology, behavior, and health, including sleep. To date, only a few and conflicting analyses have been published about the association between lunar phases and sleep. Our aim was to analyze the relationship between lunar phases and sleep characteristics. Methods In this retrospective, cross-sectional analysis, data from 319 patients who had been referred for sleep study were included. Individuals with apnea–hypopnea index ≥15/h were excluded. Socio-demographic parameters were recorded. All participants underwent one-night standard polysomnography. Associations between lunar cycle (new moon, full moon and alternate moon) and sleep parameters were examined in unadjusted and adjusted models. Results Fifty-seven percent of patients were males. Mean age for men was 45 ± 14 years and 51 ± 12 years for women. In total, 224 persons had their sleep study done during alternate moon, 47 during full moon, and 48 during new moon. Full moon was associated with lower sleep efficiency [median (%) (IQR): new moon 82 (18), full moon 74 (19), alternate moon 82 (15); P 0.001], less deep sleep [median (%) (IQR): new moon 9 (9), full moon 6 (4), alternate moon 11 (9); P 0.001], and increased REM latency [median (min) (IQR): new moon 98 (74), full moon 137 (152), alternate moon 97 (76); P 0.001], even after adjustment for several covariables. Conclusion The results are consistent with a recent report and the widely held belief that sleep characteristics may be associated with the full moon.

Objectives In aging populations, the prevalence of neurological disorders increases, which imposes high population burden in terms of mortality, disability, and impaired quality of life. The aim of this study was to assess the prevalence of common neurological disorders and signs and their association with functioning and mortality in an elderly general population. Materials and methods We used data from the Memory and Morbidity in Augsburg Elderly (MEMO) project, a population-based study of 385 individuals aged ≥65. The prevalence of neurological disorders and signs was assessed by physical examination and medical interview. The basic and instrumental activities of daily living were assessed (ADL, IADL). We assessed the association of neurological disorders and signs with everyday functioning and prospectively analyzed their relationship with mortality. Results We observed considerably impaired functioning for cases with stroke, TIA, PD, and mild motor parkinsonian signs (MMPS). All-cause mortality was significantly increased in participants with stroke and MMPS, even after adjusting for co-variables (HR = 2.71 and 1.80, respectively). Conclusions We found that not only specific neurological disorders, but also earlier symptoms are related to impaired functioning and predict mortality in the elderly. These findings have potential clinical relevance for screening and early detection of individuals at risk.

Red cell distribution width (RDW), a parameter routinely reported as part of the complete blood count, is associated with increased morbidity and mortality risk in different patient populations. No published data are available about the association between RDW and mortality in kidney transplant recipients.We collected socio-demographic, clinical parameters, medical and transplant history and laboratory data at baseline in 723 prevalent kidney transplant recipients between June and October 2008 [mean age 51 ± 13 (SD) years, 56 % men, 21 % diabetics]. Associations between baseline RDW values and all-cause mortality over 3 years were examined in unadjusted and adjusted models.Increasing RDW was associated with increased mortality in both unadjusted [(HR(1 % increase) = 1.63; 95 % CI 1.41-1.89) and (HR(median) = 2.74; 95 % CI 1.68-4.48)] and fully adjusted models [(HR(1 % increase) = 1.60; 95 % CI 1.27-1.89) and (HR(median) = 1.33; 95 % CI 0.76-2.35)]. In reclassification analyses, RDW improved the predictive value of all-cause mortality prediction models [the net reclassification improvement (NRI) was 0.189; p0.001].RDW, a cheap and readily available but largely neglected parameter independently, predicts mortality in prevalent kidney transplant recipients and could potentially been used in everyday risk assessment of kidney transplant recipients.

Red cell distribution width (RDW), a measure of heterogeneity in the size of circulating erythrocytes, reportedly predicts mortality. Similarly to RDW, impaired renal function is also associated with inflammation and protein-energy wasting. This study assessed if renal function is associated with RDW independent of relevant confounders in stable kidney transplant recipients. We examined the association between RDW and estimated glomerular filtration rate (eGFR) in a cohort of 723 prevalent kidney transplanted recipients who were not receiving erythropoietin-stimulating agents. Associations were examined in regression models adjusted for age, sex, comorbidity, blood haemoglobin, iron indices, markers of nutritional status and inflammation, markers of bone and mineral metabolism and the use of immune suppressants. Lower eGFR was significantly associated with higher RDW (r = -0·382, P

Summary Background and objectives Adiponectin (ADPN), an adipose tissue–derived hormone, has protective properties with respect to atherogenesis, inflammation, and energy homeostasis. Its beneficial role has not been consistent in patients with CKD or those undergoing dialysis. Design, setting, participants, & measurements This study examined the association of plasma ADPN levels in 987 prevalent kidney transplant recipients (mean age ± SD, 51.0±12.8 years; estimated GFR, 52.8±21.9 ml/min per 1.73 m 2 ; median time since transplant, 78 months) on all-cause mortality and death-censored graft failure. Patients were enrolled between February and August 2007 and were followed for a median of 51 months (interquartile range, 49–53 months). Using Cox proportional hazard models, the association of log-transformed plasma adiponectin was studied, with and without adjustment for demographic variables, baseline GFR, markers of inflammation, and cardiovascular risk factors. Results At baseline, patients in the lowest ADPN tertile were significantly more likely to be male; to be smokers; to have a higher baseline GFR, lower systolic BP, and lower HDL cholesterol level; and to have higher body mass index, abdominal circumference, C-reactive protein level, and total cholesterol level. The adjusted hazard ratio for death with elevated plasma ADPN (per natural log) was 1.44, and there was no significant interaction with any relevant cardiovascular risk subgroups ( i.e. , advanced age; diabetes; or elevated body mass index, waist circumference, C-reactive protein, or Framingham risk score). The hazard for death-censored graft failure was nonsignificant at 1.03. Conclusion Elevated ADPN levels are associated with higher risk for death but not allograft failure in prevalent kidney transplant recipients.

Inhibitors of the mammalian target of rapamycin (mTOR), sirolimus and everolimus, reduce the incidence of acute rejection following kidney transplantation, but their impact on clinical outcomes beyond 2 years after transplantation is unknown. We examined risks of mortality and allograft loss in a prospective observational study of 993 prevalent kidney transplant recipients who enrolled a median of 72 months after transplantation. During a median follow-up of 37 months, 87 patients died and 102 suffered allograft loss. In the overall population, use of mTOR inhibitors at enrollment was not associated with altered risk of allograft loss, and their association with increased mortality was of borderline significance. However, history of malignancy was the strongest predictor of both mortality and therapy with an mTOR inhibitor. Among patients without a history of malignancy, use of mTOR inhibitors was associated with significantly increased risk of mortality in propensity score-adjusted (hazard ratio [HR] 2.6; 95% CI, 1.2, 5.5; p = 0.01), multivariable-adjusted (HR 3.2; 95% CI, 1.5, 6.5; p = 0.002) and one-to-one propensity score-matched analyses (HR 5.6; 95% CI 1.2, 25.7; p = 0.03). Additional studies are needed to examine the long-term safety of mTOR inhibitors in kidney transplantation, especially among recipients without a history of malignancy.

Chronic kidney disease has profound effects on the health-related quality of life (HRQoL) of patients, with serious physiological, psychological and socio-economic implications. The co-occurrence of protein-energy wasting and inflammation in end-stage renal disease patients is associated with worse HRQoL and increased mortality. We designed this study to examine the relationship between nutritional and inflammatory status and HRQoL in kidney transplant recipients. Data from 100 randomly selected kidney transplant patients were analyzed in a cross-sectional survey. Socio-demographic parameters, laboratory results, transplantation-related data, comorbidities, medication and malnutrition-inflammation score (MIS) (Kalantar Score) were tabulated at baseline. Patients completed the Kidney Disease Quality of Life-SF (KDQoL-SF™) self-administered questionnaire. Mean age was 51 ± 13 years, median (interquartile range, IQR) time since transplantation 66 (83) months, 57% were men, and 19% had diabetes. The median (IQR) MIS was 3 (3). The MIS significantly and negatively correlated with almost all HRQoL domains analyzed, and this association remained significant in multivariate linear regression analysis for the log-transformed scores on energy/fatigue (β = −0.059 P

In patients on dialysis, the results of studies examining the association between sleep disorders and inflammation are controversial. We assessed the association between inflammatory markers and different sleep disorders in a large sample of kidney transplant recipients. Cross-sectional study of 100 randomly selected kidney transplant patients who underwent one-night polysomnography (“sleep disorders evaluation in patients after kidney transplantation study”) to diagnose obstructive sleep apnea (OSA) and periodic limb movements in sleep (PLMS). Athens Insomnia Scale (AIS) was utilized to assess the prevalence of insomnia. Sociodemographic information and data about medication, comorbidity and laboratory parameters were collected. Levels of inflammatory markers, such as C-reactive protein, serum albumin, white blood cell count, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), were measured. The mean age was 51 ± 13 years, 43% were women, and the prevalence of diabetes was 19%. We found no significant difference in the levels of inflammatory markers between patients with versus without OSA and PLMS. Apnea–hypopnea index showed a significant association with white blood cell count (ρ = 0.23), and weak (ρ

Racial and ethnic disparities among North American patients with chronic kidney disease have received significant attention. In contrast, little is known about health-related outcomes of patients with end-stage renal disease among the Roma minority, also known as gypsies, compared to Caucasian individuals. We prospectively assessed the association between Roma ethnicity and long-term clinical outcomes in kidney transplant recipients. In a prevalent cohort of renal transplant recipients, followed up over a median of 94 months, we prospectively collected socio-demographic, medical (and transplant related) characteristics and laboratory data at baseline from 60 Roma and 1,003 Caucasian patients (mean age 45 (SD = 11) and 49 (SD = 13) years, 33 and 41% women, 18 and 17% with diabetes mellitus, respectively). Survival analyses examined the associations between Roma ethnicity and all-cause mortality and death-censored graft loss or death with functioning renal allograft. During the follow-up period, 341 patients (32%) died. Two-hundred eighty (26%) patients died with a functioning graft and 201 patients (19%) returned to dialysis. After multivariable adjustments, Roma ethnicity was associated with 77% higher risk of all-cause mortality (Hazard Ratio (HR): 1.77; 95% confidence interval (CI): 1.02, 3.07), two times higher risk of mortality with functioning graft (2.04 [1.17–3.55]) and 77% higher risk of graft loss (1.77 [1.01–3.13]), respectively. Roma ethnicity is independently associated with increased mortality risk and worse graft outcome in kidney transplant recipients. Further studies should identify the factors contributing to worse outcomes among Roma patients.

A large number of studies have examined associations between brain-derived neurotrophic factor (BDNF) gene polymorphisms and depressive symptoms. However, results still remain controversial. Recent studies suggested a significant age and gender effect on the heritability of depression. The potential neurobiological pathways that could possibly mediate this relationship have not been examined so far. Since BDNF is involved in the regulation of neurotransmitter production, a mediating role of neurotransmitters seems plausible. The present study aims to examine the association between three common BDNF single-nucleotid polymorphisms (SNPs; rs7103411, rs7124442, and rs6265) and depressive symptoms in a community-based elderly population taking into account the serum levels of four neurotransmitters, serotonin, dopamine, adrenalin, and noradrenalin, as potential mediating factors. We also examined whether age and gender had a modifying effect on this association. We collected and analyzed the genetic and laboratory data as well as Center for Epidemiologic Studies-Depression scores of 350 community-dwelling elderly individuals (aged 65+ years). We found that the BDNF rs6265 polymorphism was related to the severity of depressive symptoms, and that this association was independent of neurotransmitter levels. Stratified analyses showed that this association was restricted to older individuals (≥74 years) and men. The associations of SNPs rs7103411 or rs7124442 SNP with depressive symptoms were not statistically significant. This study importantly adds to the existing literature by affirming previous assumptions on an age and gender difference in the relation between BDNF genotype and depression. We moreover first-time report a missing mediating role of neurotransmitters in this association.

Background The combination of chronic malnutrition and inflammation, often termed malnutrition-inflammation complex syndrome or protein-energy wasting, is common in patients with chronic kidney disease. It is associated with increased mortality in patients on maintenance dialysis therapy. We assessed the association of malnutrition-inflammation score (MIS) with all-cause mortality and death-censored transplant loss or death with a functioning transplant in a sample of kidney transplant recipients. Study Design Prospective prevalent cohort study. Setting & Participants Data from 993 prevalent transplant recipients were analyzed. Sociodemographic parameters, laboratory data, medical and transplant history, comorbid conditions, estimated glomerular filtration rate, and MIS were tabulated at baseline and annually thereafter. Predictor MIS, a 30-point scale expressed per 1 standard deviation (1 SD) unit or categorized as 8. The MIS is derived from 10 components, each with 4 levels of severity from 0 (normal) to 3 (severely abnormal). Higher score reflects more severe degree of malnutrition and inflammation status. Outcomes All-cause mortality and death-censored transplant loss or death with a functioning transplant. Association of MIS with total mortality was assessed using time-dependent Cox regression analysis, and the association of MIS with death-censored transplant loss or death with a functioning transplant was assessed using semiparametric competing-risks regression analysis. Results Mean age was 51 ± 13 years, 57% of patients were men, and 21% had diabetes. Percentages of patients in the MIS categories 8 were 40%, 32%, 20%, and 8%, respectively. In multivariable time-dependent Cox regression analyses, time-varying MIS score was a significant predictor of all-cause mortality (HR per 1-SD increase, 1.59; 95% CI, 1.37-1.85), death with a functioning transplant (HR per 1-SD increase, 1.48; 95% CI, 1.23-1.78), and death-censored transplant loss (HR per 1-SD increase, 1.34; 95% CI, 1.04-1.71). Compared with MIS 8 were 1.53 (95% CI, 0.74-3.15), 3.66 (95% CI, 1.87-7.14), and 6.82 (95% CI, 3.34-13.91), respectively. Limitations Single-center study, small number of outcomes. Conclusions The MIS, a simple tool to assess the presence of malnutrition-inflammation complex syndrome, predicts mortality in kidney transplant recipients.

Cognitive aging processes are underpinned by multiple processes including genetic factors. The brain-derived neurotrophic factor (BDNF) has been suggested to be involved in age-related cognitive decline in otherwise healthy individuals. The gender-specific role of the BDNF gene in cognitive aging remains unclear. The identification of genetic biomarkers might be a useful approach to identify individuals at risk of cognitive decline during healthy aging processes. The aim of this study was to investigate the associations between three single-nucleotide polymorphisms (SNPs) in the BDNF gene and domains of cognitive functioning in normal cognitive aging. The sample, comprising 369 participants (M = 72.7 years, SD = 4.45 years), completed an extensive neuropsychological test battery measuring memory, motor function, and perceptual speed. The relationships between the SNPs rs6265, rs7103411, and rs7124442 and cognitive domains were examined. While significant main effects of BDNF SNPs on cognitive function were found for the association between rs7103411 and memory performance, gender-specific analyses revealed for females significant main effects of rs7103411 for memory and of rs6265 for perceptual speed independent of the APOE*E4 status and education. The finding for the association between rs6265 and perceptual speed in females remained significant after Bonferroni correction for multiple comparisons. None of the analyses showed significant results for males. This study is the first to implicate that the SNPs rs6265 and rs7103411 affect cognitive function in the elderly in a gender-specific way.

Background. Anemia and mineral and bone disorders (MBD) are both important and common complications in kidney transplant recipients. Studies in patients with chronic kidney disease indicated a possible independent association of higher serum phosphorus with anemia, but similar associations have not been examined in kidney transplant recipients. We hypothesized that higher serum phosphorus is associated with anemia independent of other components of MBD. Methods. We examined the association of serum phosphorus with hemoglobin level and the prevalence of anemia in a prevalent cohort of 992 kidney transplant recipients in a single outpatient transplant center. Associations were examined in linear and logistic regression models with adjustment for demographic and comorbid conditions for various known risk factors of anemia, including measures of iron deficiency, inflammation, and components of MBD including serum levels of 25(OH) vitamin D, parathyroid hormone, and fibroblast growth factor 23. Results. In multivariable adjusted regression models, a 1 standard deviation (0.8 mg/dL) higher serum phosphorus level was associated with 0.26 g/dL lower blood hemoglobin concentration (95% confidence intervals ―0.36 to ―0.15, P

Background/Aims: Elevated parathyroid hormone (PTH) is used to diagnose high turnover bone disease in chronic kidney disease (CKD). The diagnostic accuracy of PTH in kidney transplant recipients with CKD is unknown. Methods: We examined kidney transplant recipients with CKD stages 3 (n = 498) and 4 (n = 141) to determine the sensitivity and specificity of the Kidney/Dialysis Outcome Quality Initiative (K/DOQI)-recommended PTH levels in detecting elevated serum β-CrossLaps (CTX) or osteocalcin (OC) levels. We performed receiver-operator curve analyses to determine CKD stage-specific PTH levels that provide optimal diagnostic accuracy. Results: PTH below the lower limits of the K/DOQI ranges (35 and 70 pg/ml in CKD stages 3 and 4, respectively) showed sensitivity of >90% in diagnosing increases in biochemical markers. The upper limits (70 and 110 pg/ml), however, showed poor specificity. A specificity of >90% for detecting increased biochemical markers was seen with PTH of >140 and >240 pg/ml in CKD stages 3 and 4, respectively. Conclusion: Currently applied cutoffs for PTH in kidney transplant recipients with CKD stages 3 and 4 do not appear to adequately detect increased biochemical markers of bone turnover. Diagnostic uncertainty exists in patients with CKD stage 3 and PTH between 35 and 140 pg/ml, and CKD stage 4 and PTH between 70 and 240 pg/ml.

Background and objectives: Obesity is associated with increased parathyroid hormone (PTH) in the general population and in patients with chronic kidney disease (CKD). A direct effect of adipose tissue on bone turnover through leptin production has been suggested, but such an association has not been explored in kidney transplant recipients. Design, setting, participants, & measurements: This study examined associations of serum leptin with PTH and with biomarkers of bone turnover (serum beta crosslaps [CTX, a marker of bone resorption] and osteocalcin [OC, a marker of bone formation]) in 978 kidney transplant recipients. Associations were examined in multivariable regression models. Path analyses were used to determine if the association of leptin with bone turnover is independent of PTH. Results: Higher leptin levels were associated with higher PTH and lower vitamin D levels, and adjustment for vitamin D attenuated the association between leptin and PTH. However, higher leptin was also significantly associated with lower levels of the bone turnover markers: 1 SD higher leptin was associated with 0.13 lower log-OC (-0.17, -0.08, P

Higher body mass index (BMI) appears paradoxically associated with better outcomes in patients with chronic kidney disease. Whereas higher BMI reflects both increased visceral and subcutaneous fat and/or muscle mass, a combined assessment of BMI and waist circumference may enable differentiation of visceral adiposity from muscle and/or nonvisceral fat mass. We examined the association of BMI and waist circumference with all-cause mortality in a prospective cohort of 993 kidney transplant recipients. Associations were examined in Cox models with adjustment for demographic and comorbid conditions and for inflammatory markers. Unadjusted death hazard ratios (95%CI) associated with one standard deviation higher BMI and waist circumference were 0.94 (0.78, 1.13), p = 0.5 and 1.20 (1.00, 1.45), p = 0.05, respectively. Higher BMI was associated with lower mortality after adjustment for waist circumference (0.48 [0.34, 0.69], p < 0.001), and higher waist circumference was more strongly associated with higher mortality after adjustment for BMI (2.18 [1.55-3.08], p < 0.001). The associations of waist circumference with mortality remained significant after additional multivariable adjustments. Higher BMI and waist circumference display opposite associations with mortality in kidney transplant recipients. Waist circumference appears to be a better prognostic marker for obesity than BMI.

Background: Chronic protein-energy wasting, termed malnutrition-inflammation complex syndrome, is frequent in patients with chronic kidney disease and is associated with anemia, morbidity, and mortality in patients on maintenance dialysis therapy. The Malnutrition-Inflammation Score (MIS) recently has been developed and validated in dialysis patients. Study Design: Observational cross-sectional study. Setting & Participants: 993 prevalent kidney transplant recipients. Predictor: MIS computed from change in body weight, dietary intake, gastrointestinal symptoms, functional capacity, comorbid conditions, decreased fat store/Systemic Global Assessment, signs of muscle wasting/Systemic Global Assessment, body mass index, serum albumin level, and serum transferrin level. Outcomes: Markers of inflammation and malnutrition, including serum C-reactive protein, interleukin 6, tumor necrosis factor alpha, serum leptin, prealbumin, body mass index, and abdominal circumference. The relationship was modeled by using structural equation models. Results: Mean age was 51 +/- 13 years, 57% were men, and 21% had diabetes. Median time from transplant was 72 months. MIS significantly correlated with abdominal circumference (r = -0.144), serum C-reactive protein level (r = 0.094), serum interleukin 6 level (r = 0.231), and serum tumor necrosis factor alpha level (r = 0.102; P

Pulse pressure (PP) reflects increased large artery stiffness, which is caused, in part, by arterial calcification in patients with chronic kidney disease. PP has been shown to predict both cardiovascular and cerebrovascular events in various patient populations, including kidney transplant (KTX) recipients. Osteoprotegerin (OPG) is a marker and regulator of arterial calcification and it is related to cardiovascular survival in hemodialysis patients. Here we tested the hypothesis that OPG is associated with increased pulse pressure. We cross-sectionally analyzed the association between serum OPG and PP in a prevalent cohort of 969 KTX patients (mean age: 51 +/− 13 years, 57% male, 21% diabetics, mean eGFR 51 +/− 20 ml/min/1.73 m2). Independent associations were tested in a linear regression model adjusted for multiple covariables. PP was positively correlated with serum OPG (rho = 0.284, p

The metabolic fate of deramciclane [(1R,2S,4R)-(-)-2-phenyl-2-(2'-dimethylamino-ethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane], a new anxiolytic drug candidate, has been determined in rat, mouse, rabbit, dog, and human hepatocytes. Rat and rabbit cells were the most active, whereas the rate of metabolism was quite slow in human hepatocytes. During biotransformation, deramciclane underwent side chain modification and oxidation at several positions of the molecule. The side chain modification led to the formation of N-desmethyl deramciclane and phenylborneol. The oxidation of deramciclane resulted in several hydroxy-, carboxy-, and N-oxide derivatives. The hydroxylation took place at primary or secondary carbons of the camphor ring as well as at the side chain; furthermore, dihydroxylated derivatives were also found. The side chain-modified metabolites were also oxidized to hydroxy- or carboxy-derivatives. Conjugation of phase I metabolites, as a route of elimination, was also observed in rat, rabbit, and dog hepatocytes. Although there were some species differences in biotransformation of deramciclane, it was concluded that phase I metabolism in human liver cells seemed to be similar to the metabolism in the hepatocytes isolated from rat. With careful approach, the rat model may be considered to be predictive for human metabolism of deramciclane.

Objective Poor sleep may be a risk factor for obesity. Previous studies have mainly investigated the effects of sleep duration on body mass index, but research considering overall sleep quality and other anthropometric measures is scarce. The aim of this study was to examine the association between sleep quality and different measures of obesity (general obesity, abdominal obesity, body composition) in a population-based sample of adults. Methods The study included 753 participants aged 35–65 years from the BiDirect Study, conducted in Munster, Germany. Participants completed the Pittsburgh Sleep Quality Index (PSQI) on sleep characteristics. Weight, height, and waist circumference were measured by trained study nurses. Body composition (fat mass and fat-free mass) was assessed using bioelectrical impedance analysis. The cross-sectional relationship between sleep quality and measures of obesity was investigated using logistic regression analysis. Results Among the participants, 65.3% reported good (PSQI ≤ 5) and 34.7% poor (PSQI > 5) sleep quality. We observed a significant association of poorer sleep quality assessed by the continuous PSQI score with general obesity and high body fat (for both, odds ratio = 1.07, 95% confidence interval = 1.01–1.13), adjusted for socio-demographic and lifestyle factors. Further adjustment for depressive symptoms and somatic comorbidities attenuated the relationship. The observed association was mainly driven by the PSQI components sleep latency, sleep disturbances, and daytime dysfunction. Conclusions The present study suggests that poor sleep quality may predict obesity and high body fat mass among adults. However, a causal relationship still has to be confirmed by prospective studies with objective measurements of sleep and obesity.

Angiopoietin 2 (Angpt2) impairs endothelial function by preventing angiopoietin 1 from binding to their common endothelial-specific receptor Tie2. Here, we examined whether circulating Angpt2 predicts outcome in kidney transplant recipients. For this case-cohort study, we selected 130 kidney transplant recipients who had died or returned to dialysis within the first 2 years of follow-up of our cohort study, as well as 130 age- and gender-matched kidney transplant recipients without an event (controls) from a total of 993 kidney transplant recipients. The total of 260 selected patients were followed in median 4 years. Serum Angpt2 at baseline was measured using an in-house immunoluminometric assay. Median Angpt2 concentrations were significantly higher in patients who died [median (interquartile range--IQR) 3.6 (2.8-5.9) ng/ml] as compared to patients who did not die during the study period [2.8 (2.1-4.1) ng/ml; P < 0.001]. Ln (natural log) Angpt2 levels correlated positively with C-reactive protein levels (r = 0.315, P < 0.001) and the Charlson Comorbidity Index (r = 0.188, P = 0.002) and were inversely associated with eGFR (r = -0.301, P < 0.001) hemoglobin (r = -0.269, P < 0.001), and serum albumin concentrations (r = -0.382, P < 0.001). On multivariate analyses, baseline Angpt2 levels independently predicted all-cause mortality (multivariable-adjusted hazard ratio associated with one natural log unit higher Angpt2 level: 1.70 (95% confidence interval: 1.10-2.61)). In our analysis, circulating Angpt2 was an independent predictor of all-cause mortality in stable, prevalent kidney transplant recipients.

Background There is evidence for neuropsychological dysfunction in depression among adult and elderly participants but little research has been conducted on the neuropsychological functioning of youth with depression. The aim of the present study was to investigate the neuropsychological functioning of outpatient young participants with depression. Methods Computerised neuropsychological tests requiring executive functioning, working memory, attention, verbal memory and learning, planning, and visuospatial skills were carried out in a sample of 13–25 year-olds with a lifetime history of non-psychotic major depression (n = 32) and in healthy age balanced controls (n = 65). Psychiatric diagnoses were ascertained using the MINI International Neuropsychiatric Interview. Results Participants with current or previous major depressive disorder demonstrated impairments in executive function tasks requiring conceptual skills and set-shifting, attention and working memory. However, planning skills were found to be largely intact. Positive affect was associated to better attention, working memory and verbal learning in depressed participants, independently from gender and education. Limitations The results may be affected by the small sample size and heterogeneity of the sample. Conclusion The findings from this study indicate, and are one of the first to identify, that young subjects aged between 13 and 25, with a lifetime history of depression, have impaired executive and working memory functioning.

Summary Background and objectives Posttransplant anemia is frequently reported in kidney transplant recipients and is associated with worsened patient survival. Similar to high erythropoiesis-stimulating agent requirements, resistance to endogenous erythropoietin may be associated with worse clinical outcomes in patients with ESRD. We examined the association between serum erythropoietin levels and mortality among kidney transplant recipients. Design, setting, participants, & measurements We collected sociodemographic, clinical, medical, and transplant history and laboratory data at baseline in 886 prevalent kidney transplant recipients (mean age 51 13 [SD] years, 60% men, 21% diabetics). A solid-phase chemiluminescent immunometric assay was used to measure serum erythropoietin. Cox proportional hazards regression was used to model the association between baseline serum erythropoietin levels and all-cause mortality risk. Results During the median 39-month follow-up, 99 subjects died. The median serum erythropoietin level was 10.85 U/L and hemoglobin was 137 16 g/L. Mortality rates were significantly higher in patients with higher erythropoietin levels (crude mortality rates in the highest to lowest erythropoietin tertiles were 51.7, 35.5, and 24.0 per 1000 patient-years, respectively [P 0.008]). In unadjusted and also in adjusted Cox models each SD higher serum erythropoietin level significantly predicted all-cause mortality: HR1SD increase 1.22 and 1.28, respectively. In adjusted Cox models each SD higher serum erythropoietin/blood hemoglobin ratio also significantly predicted all-cause mortality: HR1SD increase 1.32. Serum erythropoietin predicted mortality in all analyzed subgroups. Conclusions In this sample of prevalent kidney transplant recipients, higher serum erythropoietin levels were associated with increased mortality. Clin J Am Soc Nephrol 6: ●●● –●●● , 2011. doi: 10.2215/CJN.05590611

An increased circulating level of fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease (CKD), but its role in transplant allograft and patient survival is unknown. We tested the hypothesis that increased FGF23 is an independent risk factor for all-cause mortality and allograft loss in a prospective cohort of 984 stable kidney transplant recipients. At enrollment, estimated GFR (eGFR) was 51 ± 21 ml/min per 1.73 m(2) and median C-terminal FGF23 was 28 RU/ml (interquartile range, 20 to 43 RU/ml). Higher FGF23 levels independently associated with increased risk of the composite outcome of all-cause mortality and allograft loss (full model hazard ratio: 1.46 per SD increase in logFGF23, 95% confidence interval: 1.28 to 1.68, P0.001). The results were similar for each component of the composite outcome and in all sensitivity analyses, including prespecified analyses of patients with baseline eGFR of 30 to 90 ml/min per 1.73 m(2). In contrast, other measures of phosphorus metabolism, including serum phosphate and parathyroid hormone (PTH) levels, did not consistently associate with outcomes. We conclude that a high (or elevated) FGF23 is an independent risk factor for death and allograft loss in kidney transplant recipients.

Depressive symptoms and the Malnutrition-Inflammation Complex Syndrome (MICS) are prevalent in patients with chronic kidney disease. The complex relationship between MICS and depression has never been studied in kidney transplanted (Tx) patients. Here we evaluate the association between the Malnutrition-Inflammation Score (MIS) (Kalantar score) and depressive symptoms in Tx patients.Cross-sectional data of 973 prevalent Tx patients were analyzed. Sociodemographic and anthropometric characteristics and clinical and laboratory data were collected, and serum levels of inflammatory markers [C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)] were measured. The Center for Epidemiologic Studies-Depression (CES-D) scale, the MIS and the Charlson Comorbidity Index (CCI) were computed. We used linear regression analysis to examine whether the relationship between MIS and CES-D score is independent from sociodemographic and laboratory parameters.The CES-D score, corrected for age, gender and estimated glomerular filtration rate weakly but significantly correlated with serum IL-6 and the CCI (0.124 and 0.103, respectively; P.05 for both) and marginally significantly with CRP (0.06; P=.06). We found a moderate correlation between CES-D score and MIS (0.262; P.001). In a multivariable linear regression model, the MIS was independently associated with the CES-D score (B=0.110; P.001).The MIS was significantly associated with depressive symptoms after adjusting for important covariables in patients after renal transplantation.

Background. Post-transplant anaemia (PTA) is common and is associated with adverse consequences. The protein-energy wasting (PEW) syndrome is associated with erythropoietin resistance in patients on maintenance dialysis. We assessed the association between PEW and PTA in a large prevalent cohort of stable kidney-transplanted patients.Methods. Data from 942 prevalent kidney-transplanted patients were analysed. Socio-demographic parameters, laboratory results, transplantation-related data and medication were obtained from the charts. Biomarkers reflecting nutritional status and inflammation [serum leptin, albumin, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and C-reactive protein] were measured. Anthropometric measures and the malnutrition-inflammation score (MIS) were also tabulated. Anaemia was defined according to the guidelines of the American Society of Transplantation.Results. Mean age was 51 ± 13 years, 57% were males and 22% had diabetes. The prevalence of PTA was 33%. The haemoglobin (Hb) level significantly and negatively correlated with the MIS (rho = − 0.316), marginally with serum TNF-α (rho = − 0.079) and serum IL-6 (rho = − 0.075) and positively with serum transferrin (r = 0.298), serum albumin (r = 0.274), abdominal circumference (r = 0.254) and serum leptin (rho = − 0.152), P < 0.05 for all. In a multivariable linear regression model, MIS was independently associated with Hb (beta = − 0.118, P = 0.004) in patients with estimated glomerular filtration rate (eGFR) lower than or equal to 60 mL/min/1.73 m 2 , but not in patients with higher eGFR.Conclusions. The MIS is independently associated with PTA in the kidney-transplanted population with eGFR lower than or equal to 60 mL/min/1.73 m 2 .

Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular morbidity in the general population. The clinical significance of OSA among kidney transplant patients is unknown. Our aim was to investigate the association of "high risk of OSA" with death-censored graft loss and mortality in a large cohort of kidney transplant recipients.Using the Berlin questionnaire 1067 prevalent kidney transplant recipients were assessed for risk of OSA. Socio-demographic variables, laboratory parameters and data about graft loss and mortality were obtained from the medical records. Multivariable-adjusted associations of OSA risk with graft loss and with all-cause mortality was assessed in competing-risks regression models.Of the 823 patients who completed the Berlin questionnaire 28% had high risk of OSA (HRO) at baseline. Patients with HRO were older (52±11 vs. 47±13years, p0.001), had a higher prevalence of diabetes (22 vs. 15%, p=0.018), worse baseline kidney function (estimated glomerular filtration rate: 46±18 vs. 51±19ml/min/1.73m(2), p=0.001) and higher BMI (27±5 vs. 24±4kg/m(2), p0.001). In multivariate models HRO was an independent predictor of graft loss among females after adjusting for age, comorbidity, hypertension, BMI, kidney function, duration of chronic kidney disease, other laboratory parameters and transplant-related data (HR=3.05; CI: 1.24-7.51; p=0.015), while HRO did not predict graft survival among males. HRO at baseline was not independently associated with all-cause mortality in the sample.High risk of OSA is an independent predictor of graft loss among female kidney transplant patients.

Background and objectives: We assessed the prevalence of obstructive sleep apnea (OSA) and its clinical correlates in a large sample of patients who received a kidney transplant (Tx). We also compared the prevalence of the disorder between dialysis patients who were on the waiting list for a Tx (WL) and Tx patients. Design, setting, participants, & measurements: This was a cross-sectional study of 100 Tx and 50 WL patients who underwent one-night polysomnography (SLeep disorders Evaluation in Patients after kidney Transplantation [SLEPT] Study). Sociodemographic information and data about medication, comorbidity, and laboratory parameters were collected. Results: The prevalence of mild (apnea-hypopnea index [AHI] >5/h and 15/h and 30/h) was 18, 11, and 14% in the Tx group and 28, 16, and 10% in the WL group, respectively. The AHI was significantly correlated with age ( 0.34), body mass index ( 0.45), neck circumference ( 0.4), abdominal circumference ( 0.51), and hemoglobin ( 0.24) in the Tx group. The proportion of Tx patients who were treated with three or more antihypertensive drugs was significantly higher in the OSA group (56 versus 31%; P 0.022). Despite taking significantly more antihypertensive drugs, the average systolic BP was still higher in patients with versus without OSA (147 21 versus 139 18 mmHg; P 0.059). Conclusions: The prevalence of OSA is similar in Tx and WL patients and it may contribute to presence of hypertension in patients who receive a Tx. Clin J Am Soc Nephrol 5: 125–132, 2010. doi: 10.2215/CJN.04030609

Impaired kidney function is common in kidney-transplanted patients and complications of chronic kidney disease (CKD), such as mineral and bone disorders (MBD) are also prevalent in this population. Similarly to other stages of CKD, increasing evidence supports the association between MBD and cardiovascular risk after kidney transplantation as well. Still, little is known about the prevalence, clinical correlates of MBD and its management in transplanted patients. In this study, we aimed to examine the characteristics of MBD and its associations with clinical parameters in a large prevalent cohort of patients after kidney transplantation.Nine hundred and ninety stable patients followed at a single kidney transplant outpatient clinic were included in the study. Detailed medical history, demographic data and routine laboratory results, including Ca, P and intact PTH were collected. Estimated GFR was calculated using the abbreviated MDRD formula, patients were stratified into three groups based on eGFR. Target levels for Ca, P and iPTH were based on CKD stages according to the NKF-K/DOQI guidelines. Standard statistical procedures, binomial and multinomial regressions were used in the analysis.The mean age was 51 years, 57% were males and 21% were diabetic, with 72 months (median) post-transplantation. Most of the patients were in CKD stage 3. Serum phosphorus showed strong negative correlation with graft function in CKD stages 4-5 (r = -0.633, P0.001). Hyperphosphatemia was independently associated with the time spent on dialysis before transplantation, serum iPTH and CKD stages 4-5. iPTH showed negative correlation with eGFR in CKD stages 3-5 (rho = -0.289, P0.001) and weak positive correlation with time spent on dialysis prior to transplant (rho = 0.114, P0.001). Both hyperparathyroidism (42%) and relative hypoparathyroidism (15%) were frequent. The prescription of P-binders (6%) and vitamin D analogs (33%) was sporadic.Disturbances of bone and mineral metabolism after transplantation are prevalent and are strongly correlated with the kidney function, similarly to non-transplanted CKD patients. MBD in this population is not adequately managed.

Restless legs syndrome (RLS) is reportedly associated with depression. This association may be mediated by both sleep-dependent and sleep-independent mechanisms. Here we analyze the association between RLS and depressive symptoms in patients with chronic kidney disease (CKD). We also assessed whether the relationship is independent of insomnia. In a cross-sectional study, socio-demographic parameters, laboratory data, and medical history were collected from 788 kidney transplant patients and 161 dialyzed patients. Insomnia, depression, and the presence of RLS symptoms were assessed with standard questionnaires. Patients with probable RLS had a higher prevalence of depressive symptoms than those without RLS (56% vs. 22% with vs. without RLS, respectively; P

Background. Obstructive sleep apnoea syndrome (OSAS) is much more prevalent in patients on dialysis than in the general population. Our aim was to assess for the first time the prevalence of patients with a high risk for OSAS and its clinical correlates in a large sample of kidney transplanted patients. We also wanted to compare the prevalence of the disorder between waitlisted dialysis patients (WL) and kidney transplanted patients (Tx). Methods. One thousand sixty-seven kidney transplanted patients were asked to participate in a cross-sectional survey (‘TransQoL-HU Study’). Socio-demographic data, history of renal disease, medication, comorbidity and laboratory parameters were collected at enrolment. Patients completed a battery of self-administered questionnaires including the Berlin Sleep Apnoea Questionnaire to assess risk status of OSAS. Results. The final analyses included 841 Tx and 175 WL patients. The prevalence of high risk for OSAS was similar in the transplanted group vs WL patients (27% vs 33%). In multivariate logistic regression analysis male gender, older age, lower educational status, worse kidney function, use of hypnotic drugs and comorbidity were independent predictors for high risk of OSAS in kidney transplanted patients. Conclusions. High risk for sleep apnoea is highly prevalent in the kidney transplanted population. In addition to the well-known risk factors of OSAS (male gender, obesity, use of hypnotic drugs, comorbidity), impaired kidney function was also independently associated with high risk for OSAS.

Although anemia is a known risk factor of mortality in several patient populations, no prospective study to date has demonstrated association between anemia and mortality in kidney-transplanted patients. In our prospective cohort study (TransQol-HU Study), we tested the hypothesis that anemia is associated with mortality and graft failure (return to dialysis) in transplanted patients. Data from 938 transplanted patients, followed at a single outpatient transplant center, were analyzed. Sociodemographic parameters, laboratory data, medical history and information on comorbidity were collected at baseline. Data on 4-year outcome (graft failure, mortality or combination of both) were collected prospectively from the patients' charts. Both mortality and graft failure rate during the 4-year follow-up was significantly higher in patients who were anemic at baseline (for anemic vs nonanemic patients, respectively: mortality 18% vs. 10%; p < 0.001; graft failure 17% vs 6%; p < 0.001). In multivariate Cox proportional hazard models the presence of anemia significantly predicted mortality (HR = 1.690; 95% CI: 1.115-2.560) and also graft failure (HR = 2.465; 95% CI: 1.485-4.090) after adjustment for several covariables. Anemia, which is a treatable complication, is significantly and independently associated with mortality and graft failure in kidney-transplanted patients.

1. Rats treated orally with [14C]mesocarb (I; 3-(1-methyl-2-phenyl[2-(14C]ethyl)-N-(phenylaminocarbonyl)sydnone imine) (50 mg/kg) excrete 35% of the radioactivity in 24 h urine and 51% in 48 h urine. 2. Only traces of unchanged drug were found in urine. Hydroxy-mesocarb (II), dihydroxy-mesocarb (III), amphetamine (VII) and the conjugates of II and III account for 86% of the urinary radioactivity. 3. Cannulated male rats excrete about 40% of the radioactivity in 30 h in bile, mainly as conjugates of II and III.

Gas chromatographic analysis of steroids using Sp-2100 stationary phase revealed that all urine samples from 34 healthy children (aged 4-14 years) and from 35 adults contained 5-pregnene-3 beta, 20 alpha-diol, which was also identified by GC-MS. The extent of pregnenediol excretion continuously increased from prepuberty to adult age. The observed increase in pregnenediol excretion during prepuberty points to an enhanced biosynthetic activity of the adrenal gland in the years preceding sexual maturation.

A component was observed in the steroid spectrum of the urine of salt-loosing children with C/21-hydroxylase deficiency, which was eluted from Sp 2100 stationary phase before pregnanetriol but, unlike pregnanetriol, exhibited heat and acid stability. This component was isolated by paper chromatography and identified as 3 alpha, 20 alpha-dihydroxy-5 beta-pregnan-11-one by GC-MS and further gas chromatographic analysis. The amount of the steroid was minimal in the urine of infants, while in children submitted to substitution corticoid therapy it showed an increasing tendency, especially during puberty. The maximal value of excretion, in one case, amounted to 17% relative to total steroids. In puberty a significant excretion of 11-keto-pregnanediol indicates that under the given conditions the 11 beta-hydroxylation of steroid intermediates in the adrenals may be considerable not only at the level of 11-hydroxy-progesterone but also at that of progesterone.

Metabolism of vincamine has been studied in rats in vivo and in vitro using tritium labelled vincamine. Radioactivity was excreted with urine and faeces in an amount of about 62% during 72 h after i.v., i.p. and p.o. administration of the drug. From bile about 40% radioactivity could be recovered during 6 h following i.p. administration. Vincamine is excreted in unchanged form in an amount of 4-6%. In an in vitro system containing rat liver homogenate 6 alpha- and 6 beta-hydroxy-vincamine are formed, as their structures could be deduced from the mass spectrometric data. Rat plasma probably hydrolizes vincamine to vincaminic acid, but the presence of vincaminic acid could not be demonstrated, neither in urine nor in bile. Mass spectrometric investigations of the urinary and biliary metabolites have shown that beyond 6 alpha- and 6 beta-hydroxy-vincamine, their further oxidized form, 6-keto-vincamine also appears. 6 alpha-, 6 beta-hydroxy-vincamine, 6-keto-vincamine and vincamine are eliminated with urine and bile in part as conjugates. Among the metabolites (+)-eburnamonine (vincamone) was also found, which is supposed to be the degradation product of vincaminic acid. The identified compounds are responsible for about 70% of urinary and 30% of biliary radioactivities.