Serum Obestatin: A Biomarker of Cardiovascular and All-Cause Mortality in Hemodialysis Patients.

BACKGROUND: Recent experimental studies have suggested that obestatin, a proposed anorexigenic gut hormone and a physiological opponent of acyl-ghrelin, has protective cardiovascular effects. We tested the hypothesis that obestatin is independent of inflammatory mediators and/or acyl-ghrelin in predicting outcomes of the maintenance hemodialysis (MHD) population. METHODS: It was a 6-year cohort study on 261 MHD patients. Obestatin, acyl-ghrelin, adipokines (leptin and adiponectin), markers of inflammation and nutrition, prospective all-cause and cardiovascular mortality were studied. RESULTS: During the follow-up, 160 patients died in total, with 74 deaths due to cardiovascular causes. For each ng/mL increase in baseline obestatin level in fully adjusted models (including malnutrition-inflammation score, Interleukin-6 [IL-6], adipokines and acyl-ghrelin), the hazard for death from all causes was 0.90 (95% CI 0.81-0.99) and for cardiovascular death 0.85 (95% CI 0.73-0.99). However, these associations were more robust in the subgroup of patients aged above 71 years: 0.85 (95% CI 0.73-0.98) for all-cause death and 0.66 (95% CI 0.52-0.85) for cardiovascular death. An interaction between high IL-6 (above median) and low obestatin (below median) levels for increased risk of all-cause mortality (synergy index [SI] 5.14, p = 0.001) and cardiovascular mortality (SI 4.81, p = 0.02) emerged in the development of multivariable adjusted models. Interactions were also observed between obestatin, Tumor necrosis factor-alpha, adipokines and acyl-ghrelin, which were associated with mortality risk. CONCLUSION: Serum obestatin behaves as a biomarker for cardiovascular and all-cause mortality in MHD patients. The prognostic ability of obestatin in this regard is independent of inflammation, nutritional status, acyl-ghrelin's and adipokines' activity and is modified by age being very prominent in patients older than 71 years.

Interaction between acyl-ghrelin and BMI predicts clinical outcomes in hemodialysis patients.

BACKGROUND: Ghrelin, a gastric orexigenic peptide, and body mass index (BMI) are known as inversely associated to each other and are both linked to cardiovascular (CV) risk and mortality in maintenance hemodialysis (MHD) patients. However, it is unclear whether the interaction between ghrelin and BMI is associated with a risk of all-cause and CV death in this population. METHODS: A prospective observational study was performed on 261 MHD outpatients (39% women, mean age 68.6 ± 13.6 years) recruited from October 2010 through April 2012, and were followed until November 2014 (median follow-up-28 months, interquartile range-19-34 months). We measured acyl-ghrelin (AG) levels, appetite, nutritional and inflammatory markers, prospective all-cause and cardiovascular (CV) mortality. RESULTS: During follow-up, 109 patients died, 51 due to CV causes. A significant interaction effect of high BMI and high AG (defined as levels higher than median) on all-cause mortality was found. Crude Cox HR for the product termed BMI x AG was 0.52, with a 95% confidence interval (CI): 0.29 to 0.95 (P = 0.03). Evaluating the interaction on an additive scale revealed that the combined predictive value of BMI and AG is larger than the sum of their individual predictive values (synergy index was 1.1). Across the four BMI-AG categories, the group with high BMI and high AG exhibited better all-cause and cardiovascular mortality irrespective of appetite and nutritional status (multivariable adjusted hazard ratios were 0.31, 95% CI 0.16 to 0.62, P = 0.001, and 0.35, 95% CI 0.13 to 0.91, P = 0.03, respectively). Data analyses made by dividing patients according to fat mass-AG, but not to lean body mass-AG categories, provided similar results. CONCLUSIONS: Higher AG levels enhance the favourable association between high BMI and survival in MHD patients irrespective of appetite, nutritional status and inflammation.

Longitudinal study of leptin levels in chronic hemodialysis patients.

BACKGROUND: The influence of serum leptin levels on nutritional status and survival in chronic hemodialysis patients remained to be elucidated. We conducted a prospective longitudinal study of leptin levels and nutritional parameters to determine whether changes of serum leptin levels modify nutritional status and survival in a cohort of prevalent hemodialysis patients. METHODS: Leptin, dietary energy and protein intake, biochemical markers of nutrition and body composition (anthropometry and bioimpedance analysis) were measured at baseline and at 6, 12, 18 and 24 months following enrollment, in 101 prevalent hemodialysis patients (37% women) with a mean age of 64.6 ± 11.5 years. Observation of this cohort was continued over 2 additional years. Changes in repeated measures were evaluated, with adjustment for baseline differences in demographic and clinical parameters. RESULTS: Significant reduction of leptin levels with time were observed (linear estimate: -2.5010 ± 0.57 ng/ml/2 y; p < 0.001) with a more rapid decline in leptin levels in the highest leptin tertile in both unadjusted (p = 0.007) and fully adjusted (p = 0.047) models. A significant reduction in body composition parameters over time was observed, but was not influenced by leptin (leptin-by-time interactions were not significant). No significant associations were noted between leptin levels and changes in dietary protein or energy intake, or laboratory nutritional markers. Finally, cumulative incidences of survival were unaffected by the baseline serum leptin levels. CONCLUSIONS: Thus leptin levels reflect fat mass depots, rather than independently contributing to uremic anorexia or modifying nutritional status and/or survival in chronic hemodialysis patients. The importance of such information is high if leptin is contemplated as a potential therapeutic target in hemodialysis patients.

Objective Score of Nutrition on Dialysis (OSND) as an alternative for the malnutrition-inflammation score in assessment of nutritional risk of haemodialysis patients.

BACKGROUND: Evaluation of nutritional risk, one of the strongest predictors of morbidity and mortality in maintenance haemodialysis (HD) patients, is a difficult process especially in patients with compounding conditions that prevent subjective assessment by subjective global assessment or malnutrition-inflammation score (MIS). METHODS: In this study, we developed and characterized a score for the assessment of nutritional status in dialysis patients based solely on objectively measurable criteria. Our prospective observational cohort included 81 prevalent HD patients (53 men and 28 women) with a mean age of 64.3 +/- 11.9 years. The study period encompassed 26.9 +/- 14.3 months. The quantitative and comprehensive scoring system, named Objective Score of Nutrition on Dialysis (OSND), was calculated by combining anthropometric measurements (the change in end-dialysis dry weight in the past 3-6 months, body mass index, skinfold thickness and mid-arm circumference) with three laboratory tests: albumin, transferrin and cholesterol levels. The sum of all seven components of OSND results in a score from 5 (severely malnourished) to 32 (normal). We compared our OSND system with the accepted MIS and phase angle (PA) measurements derived by bioelectric impedance analysis. RESULTS: The OSND correlated significantly with hospitalization days (r = -0.334; P = 0.002) and frequency of hospitalization (r = -0.373; P = 0.001), as well as with lean body mass and fat mass, MIS, PA and interleukin-6 levels. The Cox proportional hazard-calculated relative risk for death for each five-unit decrease in the OSND was 2.2 (95% CI, 1.3 to 3.8; P = 0.003) comparable with the predictions provided by MIS [for each five-unit increase in MIS, hazard ratio (HR) was 1.8 with 95% CI, 1.2 to 2.8; P = 0.007] and PA (for each 1-unit decrease in PA, HR was 2.9 with 95% CI, 1.5 to 5.6; P = 0.001). CONCLUSIONS: The OSND thus provides a comprehensive scoring system with significant associations with prospective hospitalization and mortality in chronic HD patients as well as measures of nutrition and inflammation.

The cyclin kinase inhibitor p57kip2 regulates TGF-beta-induced compensatory tubular hypertrophy: effect of the immunomodulator AS101.

BACKGROUND: Compensatory tubular cell hypertrophy following unilateral nephrectomy is a cell cycle-dependent process. Our previous study showed that treatment of unilaterally nephrectomized rats with the immunomodulator AS101 partially inhibits compensatory hypertrophy of the remaining kidneys through the inhibition of IL-10-induced TGF-beta secretion by mesangial cells. The present study is focused on understanding the intracellular mechanism(s) of this phenomenon. METHODS: A total of 120 male Sprague-Dawley rats were unilaterally nephrectomized or sham-operated and treated with AS101 or PBS. Kidney weight and protein/DNA ratio were assessed for each experimental animal. The expression of TGF-beta, PCNA, CDK 2, pRb, ppRb, p21(Waf1), p27(kip1) and p57(kip2) proteins in renal tissues was determined by western blot analysis and immunohistochemistry, and the immunoprecipitation of cyclin E complexes was performed. RESULTS: Compensatory renal growth is initiated by proliferation of resident renal cells that precedes hypertrophy. Changes in TGF-beta expression were positively correlated with the amounts of p57(kip2), but not with p21(Waf1) and p27(kip1) expression in the remaining kidneys. Moreover, there was a marked abundance of p57(kip2) but not p21(Waf1) and p27(kip1) binding to the cyclin E complex in PBS-treated unilaterally nephrectomized rats compared to sham-operated animals. Treatment of uninephrectomized rats with AS101 reduced kidney weight and protein/DNA ratio, inhibited TGF-beta and p57(kip2) expression in the remaining kidneys, and decreased the level of p57(kip2) binding to cyclin E complexes. CONCLUSION: These results demonstrate that TGF-beta-induced compensatory tubular cell hypertrophy is regulated in vivo by p57(kip2) but not by the p21(Waf1) and p27(kip1) cyclin kinase inhibitor proteins.

Nutritional and inflammatory status of hemodialysis patients in relation to their body mass index.

OBJECTIVE: The study tested whether obese hemodialysis (HD) patients have a better nutritional and inflammatory state than those with overweight or normal body mass index (BMI). DESIGN: This was a single-center, cross-sectional study. SETTING AND PATIENTS: Ninety-six stable HD patients from a local HD unit were divided into 3 groups according to BMI (normal, overweight, and obese). MAIN OUTCOME MEASURES: Anthropometry, body composition by multifrequency bioelectrical impedance analysis, biochemical nutritional markers, as well as interleukins (IL-1, IL-6, and IL-10), tumor necrosis factor, leptin, and soluble leptin receptor (sOB-R) were measured. RESULTS: Serum creatinine was significantly elevated in the highest BMI category. Albumin and transferrin were significantly elevated in higher BMI groups after adjustment for age, sex, and diabetes status. The higher BMI group had greater lean body mass (P = .001) and fat mass (P = .0001), higher phase angle (PA), and lower extracellular mass-to-body-cell-mass ratio (ECM/BCM) (P < .05). Inflammatory cytokine levels were not different in the 3 BMI groups. In parallel with increasing BMI, a gradual increase in serum leptin and a trend for decreasing sOB-R were detected (P = .0001 and P = .055, respectively). Both PA (r = 0.295, P = .008) and ECM/BCM (r = -0.345, P = .002) significantly correlated with serum leptin concentration. According to a multiple linear regression analysis, with PA as the dependent variable, age (beta = 0.274, P = .008), creatinine (beta = 0.355, P = .001), and log sOB-R/leptin ratio (beta = -0.465, P = .008) were significant independent predictors of PA. CONCLUSION: HD patients with elevated BMI demonstrate better nutritional status compared to normal BMI or overweight patients, whereas the severity of inflammation is not related to BMI in HD patients.

Abdominal obesity in normal weight versus overweight and obese hemodialysis patients: Associations with nutrition, inflammation, muscle strength, and quality of life.

OBJECTIVE: The biological basis of abdominal obesity leading to more severe outcomes in patients with normal body mass index (BMI) on maintenance hemodialysis (MHD) is unclear. The aim of this study was to compare the properties of abdominal obesity in different BMI categories of patients on MHD. METHODS: We performed a cross-sectional study of 188 MHD patients (52.7% women; mean age, 69.4 ± 11.5 y) with abdominal obesity in different BMI groups using criteria from the World Health Organization. Appetite and dietary intake, body composition, handgrip strength, malnutrition inflammation score (MIS), inflammatory biomarkers, adipokines, and health-related quality-of-life (QoL) questionnaires were studied. RESULTS: According to multivariable analyses, abdominally obese patients with normal BMIs consumed less protein per day (P = 0.04); had lower measurements of surrogates of lean (P < 0.001) and fat mass (P < 0.001); and had higher total cholesterol, tumor necrosis factor-α (P < 0.05), and ratios of adiponectin to leptin (P = 0.003) than overweight and obese patients with abdominal obesity. Multivariable analyses showed no differences in handgrip strength among the study groups.The abdominally obese study participants with normal weight had significantly lower scores in role physical (P = 0.003) and pain (P = 0.04) scales after multivariable adjustments. CONCLUSIONS: Normal-weight MHD patients with abdominal obesity exhibited a more proatherogenic profile in terms of inflammatory markers and adipokine expression, lower body composition reserves, and lower physical ability than patients with abdominal obesity with overweight and obesity. This at least partially explains the abdominal obesity paradox in the MHD population in which worse clinical outcomes are seen in abdominally obese patients with normal BMIs, as opposed to overweight and obese patients who are also abdominally obese.

Age modifies the association between serum obestatin, appetite and nutritional status in maintenance hemodialysis patients.

BACKGROUND/OBJECTIVES: Increased age is strongly associated with anorexia and protein-energy wasting (PEW) in maintenance hemodialysis (MHD) population. We hypothesized that the association of obestatin, a recently discovered anorexigenic gut hormone, with appetite and nutritional status differs by age groups. SUBJECTS/METHODS: We performed a cross-sectional study on 261MHD patients. Obestatin, acyl-ghrelin, markers of inflammation (CRP, IL-6, TNF-α) and nutrition (self-reported appetite, dietary intake, biochemical nutritional parameters, and body composition) were measured. RESULTS: Obestatin was associated with appetite in multivariate analyses even after controlling for such confounders as lean body mass (LBM), IL-6 and acyl-ghrelin in patients younger than 71 years. For each ng/ml increase in obestatin levels, the odds for diminished appetite was 0.75 (95% CI: 0.59-0.96). However, these associations were not observed in patients 71 years and older. Multivariable logistic regression models (including appetite) also showed increasing odds for PEW (defined by ESPEN consensus-based criteria for the diagnosis of malnutrition) across increasing serum obestatin levels (OR: 1.51, 95% CI: 1.05-2.18) in patients 71 years and older. However, after lean body mass (LBM) was added to this model, the association between obestatin and malnutrition was abolished (OR: 1.26, 95% CI: 0.83-1.91). CONCLUSIONS: The association between serum obestatin, appetite and PEW differs depending on age in MHD patients. A positive link with appetite exists in patients younger than 71 years, whereas this relationship disappears by the age of 71. In older MHD patients, obestatin is associated with PEW through mechanisms related to LBM, but not to appetite.

A single center, open-label, randomized, parallel group study assessing the relationship between asymptomatic bacteriuria and inflammation in maintenance hemodialysis patients.

INTRODUCTION: The significance of asymptomatic bacteriuria in maintenance hemodialysis (MHD) patients remains controversial. We hypothesized that the presence of asymptomatic bacteriuria as a sole clinical manifestation of urinary tract infection (UTI) in asymptomatic MHD patient may contribute to the chronic inflammatory response. Our aim was to explore the relationship between asymptomatic bacteriuria and elevated levels of inflammatory markers in MHD patients. METHODS: A randomized open-label single center study of 114 MHD patients was conducted. Forty-six patients presented negative urine culture and 41 subjects were excluded due to different reasons. The remaining 27 patients (mean age of 71.5 ± 12.2 years, 63% men), fulfilling the criteria for having asymptomatic bacteriuria, were randomly assigned to either the treatment group (13 patients) or the observational group (14 subjects). The treatment group received 7 days of antibiotic treatment given according to bacteriogram sensitivity. After 3 months of follow-up all measurements of the study were repeated. The primary end point was change in inflammatory biomarkers from baseline by the end of the study. FINDINGS: There were no statistically significant differences in white blood cell changes (P = 0.27), ferritin (P = 0.09), C-reactive protein (P = 0.90), and interleukin-6 (P = 0.14) levels between the groups from baseline to the end of study or at the end of the study. Analyzing cross-sectional data, asymptomatic bacteriuria was found to not be a predictor of higher levels of inflammatory parameters at baseline. DISCUSSION: Asymptomatic bacteriuria is not a modifiable risk factor for chronic inflammation in the MHD population.

Geriatric nutritional risk index, muscle function, quality of life and clinical outcome in hemodialysis patients.

BACKGROUND & AIMS: The geriatric nutritional risk index (GNRI) has been reported as a useful predictor of prognosis in maintenance hemodialysis (MHD) patients, demonstrating GNRI less than 90 as a marker of a poorer nutritional status and significantly increased mortality. We tested whether GNRI as a whole associated stronger with clinical and laboratory surrogates of nutrition and inflammation, muscle function, health-related quality of life (QoL), and predicts all-cause and cardiovascular (CV) morbidity and mortality in this population better than its individual components (albumin and body weight to ideal body weight ratio). METHODS: A prospective observational study with a median follow-up of 30 months (interquartile range - 19-41 months) was performed on 352 MHD outpatients (38.0% women) with a mean age of 67.4 ± 13.2 years. All-cause and cardiovascular hospitalization and mortality, GNRI, handgrip strength (HGS), body composition parameters (anthropometry and bioimpedance) and short form 36 (SF-36) quality-of-life scores were measured. Multivariate linear regression analyses were performed to obtain adjusted correlations. Receiver operating characteristic (ROC) curves were generated and multivariate Cox proportional hazards models were applied to identify the predictive value of GNRI and its components separately. RESULTS: GNRI positively correlated with total score (r = 0.15, P < 0.05), the physical health dimension (r = 0.14, P < 0.05), the general health (r = 0.18, P < 0.01) and some other scales of the SF-36. A significant correlation of GNRI with HGS in male patients didn't stand up to multivariable adjustments. For each one unit increase in baseline GNRI levels, the first hospitalization hazard ratio (HR) after adjustments for confounders was 0.98 (95% confidence interval (CI), 0.97 to 0.99) and the first CV event HR was 0.98 (95% CI, 0.97 to 0.99); all-cause death HR was 0.97 (95% CI, 0.96 to 0.99) and CV death HR was 0.97 (95% CI, 0.95-0.99). Albumin was related to QoL and clinical outcomes with higher strength and magnitude than GNRI. CONCLUSIONS: Despite the significant relationship with clinical outcomes and QOL, GNRI is not better and is even slightly worse than albumin's performance. This raises doubts as to the clinical utility of GNRI as a prognostic tool in the MHD population.

Longitudinal Study of Serum Uric Acid, Nutritional Status, and Mortality in Maintenance Hemodialysis Patients.

BACKGROUND AND OBJECTIVES: We hypothesized that longitudinal changes in uric acid (UA) may have independent associations with changes in nutritional parameters over time and consequently, long-term survival of patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective, longitudinal cohort study of a clinical database containing the medical records of patients on maintenance hemodialysis receiving dialysis between June of 1999 and December of 2012 in a single center; 200 patients (130 men and 70 women) with a median age of 69.0 (interquartile range, 59.3-77.0) years old were included in the study. Dietary intake, biochemical markers of nutrition, anthropometric measurements, and UA levels were recorded at 0, 6, 12, 18, 24, 30, and 36 months followed by 15 additional months of clinical observations. The patients were followed until January 31, 2015 (median follow-up was 38.0 [interquartile range, 30.0-46.8] months). RESULTS: In a linear mixed effects model adjusted for baseline demographics and clinical parameters, each 1.0-mg/dl longitudinal increase in UA was associated with a 13.4% slower rate of decline in geriatric nutritional risk index (GNRI) levels over 3 years of observation (95% confidence interval [95% CI], 0.11 to 0.39; P<0.001 for UA × time interaction). UA remained associated with the rate of change in GNRI, even after controlling for C-reactive protein. During the follow-up, 87 (43.5%) all-cause and 38 (19.0%) cardiovascular deaths were reported. For each 1.0-mg/dl increase in serum UA over time, the multivariate adjusted all-cause mortality hazard ratio using Cox models with the effect of time-varying risk was 0.83 (95% CI, 0.74 to 0.95; P<0.01), which continued to be significant, even after including the baseline GNRI levels in this model: 0.89 (95% CI, 0.79 to 0.98; P=0.02). CONCLUSIONS: Longitudinal changes in serum UA seem to track with changes in nutritional status over time, and these changes are associated with survival of patients on maintenance hemodialysis. An increase in serum UA levels over time is accompanied by improvement of nutritional status and lower mortality rate.

Serum uric acid as a clinically useful nutritional marker and predictor of outcome in maintenance hemodialysis patients.

OBJECTIVE: The importance of serum uric acid (SUA) for the maintenance of a hemodialysis (MHD) population has not been well established. The aim of this study was to determine if SUA levels are associated with nutritional risk and consequently with adverse clinical outcomes in MHD patients. METHODS: This was a 2-y prospective observational study, performed on 261 MHD outpatients (38.7% women) with a mean age of 68.6 ± 13.6 y. We measured prospective all-cause and cardiovascular (CV) hospitalization and mortality, nutritional scores (malnutrition-inflammation score [MIS) and geriatric nutritional risk index (GNRI), handgrip strength (HGS), and short-form 36 (SF36) quality-of-life (QoL) scores. RESULTS: SUA positively correlated with laboratory nutritional markers (albumin, creatinine), body composition parameters, HGS (r = 0.26; P < 0.001) and GNRI (r = 0.34; P < 0.001). SUA negatively correlated with MIS (r = -0.33; P < 0.001) and interleukin-6 (r = -0.13; P = 0.04). Patients in the highest SUA tertile had higher total SF-36 scores (P = 0.04), higher physical functioning (P = 0.003), and role-physical (P = 0.006) SF-36 scales. For each 1 mg/dL increase in baseline SUA levels, the first hospitalization hazard ratio (HR) was 0.79 (95% confidence interval [CI], 0.68-0.91) and first CV event HR was 0.60 (95% CI, 0.44-0.82); all-cause death HR was 0.55 (95% CI, 0.43-0.72) and CV death HR was 0.55 (95% CI, 0.35-0.80). Associations between SUA and mortality risk continued to be significant after adjustments for various confounders including MIS and interleukin-6. Cubic spline survival models confirmed the linear trends. CONCLUSIONS: In MHD patients, SUA is a good nutritional marker and associates with body composition, muscle function, inflammation, and health-related QoL, upcoming hospitalizations, as well as independently predicting all-cause and CV death risk.

Longitudinal changes in bioimpedance phase angle reflect inverse changes in serum IL-6 levels in maintenance hemodialysis patients.

OBJECTIVE: We hypothesize that longitudinal changes in phase angle (PA) have independent associations with changes in inflammatory parameters over time and consequently with long-term survival in patients on maintenance hemodialysis (MHD). The aim of the present study was to determine the effect of change in nutritional and inflammatory parameters over time on change in PA and on subsequent mortality in patients on MHD. METHODS: A 2-y prospective longitudinal study was performed on 91 prevalent HD patients (57 men and 34 women), followed by an additional 3 y of clinical observations. Dietary intake, biochemical markers of nutrition, body composition, and interleukin (IL)-6 levels were measured at baseline and at 6, 12, 18, and 24 mo following enrollment. RESULTS: In a linear mixed-effect model adjusted for baseline demographic and clinical parameters, each pg/mL increase in IL-6 over time was associated with a decrease in PA levels of 0.001°/2-y (P = 0.003 for IL-6 × time interaction). PA remained associated with the rate of change in IL-6 even after controlling for extracellular water and fat mass. Changes in PA over time were associated with inverse linear changes in IL-6 (adjusted r = -0.32; P = 0.005) and consequently with mortality risk. For each 1° increase in PA, the crude and adjusted mortality hazard ratios using Cox models with effect of time-varying risk were 0.62 (95% confidence interval [CI], 0.54-0.71) and 0.61 (95% CI, 0.53-0.71), respectively. Additionally, longitudinal changes in PA exhibited significant associations with slopes of changes over time in main nutritional markers. CONCLUSIONS: Longitudinal changes in PA appear to be reliable in detecting changes in nutritional and inflammatory parameters over time, a combination that may contribute to the understanding of its prognostic utility.

Role of IL-10 in the progression of kidney disease.

Interleukin-10 (IL-10), a cytokine with anti-inflammatory and immunomodulatory functions, regulates the biology of B and T cells. The present review describes the role of IL-10 in normal renal physiology, during acute kidney injury and in the development of chronic renal failure. We further discuss IL-10-induced cellular and molecular pathways and their link to the progression of kidney injury.

Comparison analysis of nutritional scores for serial monitoring of nutritional status in hemodialysis patients.

BACKGROUND AND OBJECTIVES: This study aimed to compare the longitudinal performance of the malnutrition-inflammation score (MIS) and the geriatric nutritional risk index (GNRI), two nutritional scores for patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Nutritional scores, dietary intake, biochemical markers, and body composition analysis were performed at baseline and at 6, 12, and 18 months after enrollment (which took place from January through December 2006) on 75 prevalent hemodialysis patients (43% women, mean age 64.8 ± 11.9 years). The patients underwent simultaneous MIS and GNRI assessments calculated by two independent examiners from baseline. The study period was 46.8 ± 16.4 months. RESULTS: GNRI had higher interobserver agreement (weighted κ-score 0.98) than MIS (weighted κ-score 0.62). Longitudinally, a 1-unit increase in MIS was associated with a 0.41 kcal/kg per day reduction in daily energy intake (P<0.001) and with a 0.014 g/kg per day reduction in nPNA (P=0.02). GNRI did not correlate with the change over time of dietary intake. Longitudinal changes of both scores were associated with appropriate changes over time in levels of nutritional biomarkers, inflammation (IL-6), and body composition parameters. Both scores expressed significant associations with prospective hospitalization, whereas only MIS was associated with mortality in this cohort. The multivariate Cox proportional hazard ratio was 1.15 for death for each 1-unit increase in the MIS (95% confidence interval, 1.03-1.3; P=0.02). CONCLUSIONS: Both MIS and GNRI are valid tools for longitudinal assessment of hemodialysis patients' nutritional status. MIS has lower interobserver reproducibility than GNRI; however, MIS is more comprehensive than GNRI.

Decreased IGF-1 levels potentiate association of inflammation with all-cause and cardiovascular mortality in prevalent hemodialysis patients.

OBJECTIVE: Insulin-like growth factor-1 (IGF-1) and inflammation have both been linked to high cardiovascular risk and mortality in the general population, as well as in hemodialysis (HD) patients. We hypothesized that the association of low IGF-1 with chronic inflammation may increase the mortality risk in HD patients. DESIGN: We investigated the interactions between inflammatory biomarkers (IL-6 and TNF-α) and IGF-1 as predictors of death over a 4 years of follow-up (median--47 months, interquartile range--17.5-75 months) in 96 prevalent HD patients (35% women, mean age of 64.9 ± 11.6 years). RESULTS: A significant interaction effect of low IGF-1 (defined as a level less than median) and high IL-6 (defined as a level higher than median) on all-cause and cardiovascular mortality was found: crude Cox hazard ratios (HR) for the product termed IGF-1 × IL-6 were 4.27, with a 95% confidence interval (CI): 2.10 to 8.68 (P<0.001) and 7.49, with a 95% CI: 2.40-24.1 (P=0.001), respectively. Across the four IGF-1-IL-6 categories, the group with low IGF-1 and high IL-6 exhibited the worse outcome in both all-cause and cardiovascular mortality (multivariable adjusted hazard ratios were 4.92, 95% CI 1.86 to 13.03, and 14.34, 95% CI 1.49 to 137.8, respectively). The main clinical characteristics of patients in the low-IGF-1-high IL-6 group didn't differ from other IGF-1-IL-6 categorized groups besides gender that consequently was inserted in all multivariable models together with the other potential confounders. CONCLUSIONS: An increase in mortality risk was observed in HD patients with low IGF-1 and high IL-6 levels, especially cardiovascular causes.

Low serum concentration of obestatin as a predictor of mortality in maintenance hemodialysis patients.

Obestatin, a proposed anorexigenic gut hormone, has been shown to have a number of beneficial cardiotropic effects in experimental studies. We hypothesized that obestatin alteration in hemodialysis patients may link to clinical outcomes. This cross-sectional study with prospective followup for almost 4 years was performed on 94 prevalent hemodialysis patients. Obestatin, leptin, proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-6, and various nutritional markers were measured. Patients with low obestatin levels, defined as a level less than median, had a worse all-cause mortality and cardiovascular mortality. The crude all-cause (HR 2.23, 95% CI 1.17 to 4.24) and cardiovascular mortality hazard ratios (HR 4.03, 95% CI 1.27 to 12.76) in these patients continued to be significant after adjustment for various confounders for all-cause mortality. Across the four obestatin-TNF-α categories, the group with low obestatin and high TNF-α (above median level) exhibited a worse outcome in both all-cause mortality and cardiovascular mortality. Clinical characteristics of patients in low obestatin high TNF-α group did not differ from other obestatin-TNF-α categorized groups. In summary, low serum obestatin concentration is an independent predictor of mortality in prevalent hemodialysis patients. Novel interactions were observed between obestatin and TNF-α, which were associated with mortality risk, especially those due to cardiovascular causes.

Increased basal nitric oxide amplifies the association of inflammation with all-cause and cardiovascular mortality in prevalent hemodialysis patients.

PURPOSE: We tested the hypothesis that the basal nitric oxide (NO) levels in prevalent hemodialysis (HD) patients may associate with inflammatory cytokines, predisposing them to increased mortality risk. METHODS: We performed a prospective cohort study of 76 prevalent HD patients (42 % women), with a mean age of 65.3 ± 11.8 years with a follow-up for almost 4 years (median--47 months, interquartile range -19-75 months). We measured basal NO, proinflammatory cytokines (TNF-α, IL-1, IL-6, and IL-10), dietary intake, biochemical parameters of nutrition, and body composition (anthropometry and bioimpedance analysis). RESULTS: Among various cytokines studied, only IL-6 exhibited a statistically significant linear association (adjusted r = 0.31, p = 0.014) with NO. Statistical interaction analysis showed a departure from multiplicity of effects of high NO (above the median) with high IL-6 (above the median) levels: crude Cox hazard ratios for all-cause and cardiovascular mortality for the product termed IL-6 × NO were 2.73 with a 95 % CI of 1.38-5.40 (p = 0.004) and 5.03 with a 95 % CI of 1.76-14.40 (p = 0.003), respectively. Across the four IL-6 NO categories, the group with high IL-6 and high NO (above their median levels) exhibited worse outcomes in both, all-cause and cardiovascular mortality (multivariable adjusted hazard ratios were 3.06, 95 % CI of 1.24-7.54 and 3.95, 95 % CI of 1.02-15.32, respectively). CONCLUSIONS: Chronic inflammation, as measured by higher serum IL-6 levels, in combination with high basal NO is associated with worse clinical outcomes in terms of all-cause and cardiovascular death in clinically stable prevalent HD patients.

N-acetylcysteine may improve residual renal function in hemodialysis patients: a pilot study.

Clinical outcomes in chronic dialysis patients are highly dependent on preservation of residual renal function (RRF). N-acetylcysteine (NAC) may have a positive effect on renal function in the setting of nephrotoxic contrast media administration. In our recent study, we showed that NAC may improve RRF in peritoneal dialysis patients. The aim of the present study was to investigate the effect of NAC on RRF in patients treated with chronic hemodialysis. Prevalent chronic hemodialysis patients with a residual urine output of at least 100 mL/24 hours were included. The patients were administered oral NAC 1200 mg twice daily for 2 weeks. Residual renal function was assessed at baseline and at the end of treatment using a midweek interdialytic urine collection for measurement of urine output and calculation of residual renal Kt/V and glomerular filtration rate (GFR). Residual GFR was measured as the mean of urea and creatinine residual renal clearance. Each patient served as his own control. Twenty patients were prospectively enrolled in the study. Administration of NAC 1200 mg twice daily for 2 weeks resulted in significant improvement in RRF: urine volume increased from 320 ± 199 to 430 ± 232 mL/24 hours (P < 0.01), residual renal Kt/V increased from 0.19 ± 0.12 to 0.29 ± 0.14 (P < 0.01), and residual GFR increased from 1.6 ± 1.6 to 2.4 ± 2.3 mL/minute/1.73 m(2) (P < 0.01). N-acetylcysteine may improve RRF in patients treated with chronic hemodialysis.

N-acetylcysteine improves residual renal function in peritoneal dialysis patients: a pilot study.

BACKGROUND: Preservation of peritoneal membrane function and residual renal function is important for the optimal care of peritoneal dialysis patients. N-Acetylcysteine may ameliorate oxidative stress, which is thought to be involved in peritoneal membrane dysfunction. In addition, N-acetylcysteine may have a positive effect on renal function in the setting of nephrotoxic contrast media administration. The aim of this study was to investigate the effect of N-acetylcysteine on peritoneal and residual renal function in peritoneal dialysis patients. METHODS: Ten prevalent peritoneal dialysis patients were administered oral N-acetylcysteine 1200 mg twice daily for 4 weeks. At baseline and at the end of treatment, peritoneal membrane function and residual renal function were assessed using a 4.25% dextrose peritoneal equilibration test and 24-hour dialysate and urine collection for calculation of peritoneal and residual renal Kt/V and mean urea and creatinine residual renal clearance. RESULTS: No significant changes were demonstrated in peritoneal membrane function, including dialysate-to-plasma creatinine ratio, sodium sieving, and net ultrafiltration. Residual renal function improved significantly: urine volume increased from 633 ± 426 to 925 ± 552 mL/24 hours (p = 0.022), residual renal Kt/V increased from 0.56 ± 0.41 to 0.75 ± 0.47 (p = 0.037), and mean residual urea and creatinine clearance increased from 4.96 ± 3.96 to 5.95 ± 4.08 mL/min/1.73 m(2) (p = 0.059). CONCLUSIONS: N-acetylcysteine may improve residual renal function in patients treated with peritoneal dialysis.