Gregory Shapiro

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.

IL-6 Levels, Nutritional Status, and Mortality in Prevalent Hemodialysis Patients

BACKGROUND AND OBJECTIVES The influence of serum IL-6 levels on nutritional status in chronic hemodialysis (HD) patients remains to be elucidated. The present report describes a prospective longitudinal study of IL-6 levels and nutritional parameters to determine whether high IL-6 levels are independently associated with nutritional status over time in a cohort of prevalent hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 85 clinically stable hemodialysis patients (37.6% women), with a mean age of 66.5 ± 10.6 years, were studied after exclusion of patients with BMI < 20 kg/m(2) and/or serum albumin <35 g/L. IL-6, dietary energy and protein intake, and 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. Observation of this cohort was continued over 2 additional years. RESULTS IL-6 levels increased with time in both unadjusted (linear estimate: 2.57 ± 0.44 pg/ml per 2 yrs; P = 0.001) and adjusted models (linear estimate: 2.35 ± 0.57 pg/ml per 2 yrs; P = 0.049). Significant reductions of daily energy intake, laboratory markers (albumin, transferrin, cholesterol, creatinine), and body composition (fat mass) with higher IL-6 levels were observed over the duration of the longitudinal observation period. However, none of the studied parameters were associated with changes in IL-6 levels over time (IL-6-by-time interactions were NS). Furthermore, cumulative incidences of survival were correlated with the baseline serum IL-6 levels (P = 0.004 by log-rank test). Finally, for each pg/ml increase in IL-6 level, the hazard ratio for death from all causes was 1.06 (95% CI 1.01 to 1.10) after adjustment for demographic and clinical parameters. CONCLUSIONS Our results suggest that higher serum IL-6 levels are associated with all-cause mortality without additional changes in clinical and laboratory markers of nutritional status in clinically stable HD patients.

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.

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.

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

Background/objectivesIncreased 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/methodsWe 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.ResultsObestatin 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).ConclusionsThe 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.

LONGITUDINAL CHANGES IN PHASE ANGLE REFLECT CHANGES IN SERUM IL-6 LEVELS IN MAINTENANCE HEMODIALYSIS PATIENTS

We hypothesized that longitudinal changes in phase angle (PA) may have independent associations with changes in inflammatory parameters over time and consequently with long-term survival in maintenance hemodialysis (MHD) patients.Dietary energy and protein intake, biochemical markers of nutrition, body composition (anthropometry and bioimpedance analysis) and IL-6 as inflammatory marker, 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 3 additional years. Longitudinally, 1O increase in PA over time, controlling for demographic and clinical parameters, was associated with a delay in longitudinal elevation of IL-6 (linear estimate: -2.11 (95% CI: -3.47; -0.75) pg/ml/mo; p=0.002 for PA X Time interaction). A decrease or increase in PA over time was associated with inverse linear changes in IL-6 levels (adjusted r=-0.305, p=0.005) and correspondingly with higher or lower death risk. For each 1O increase in PA, the crude and adjusted mortality hazard ratios using Cox models with effect of time varying risk were 0.62 (95% CI: 0.54; 0.71) and 0.61 (95% CI: 0.53; 0.71), respectively. In conclusion, longitudinal changes in PA appeared to be reliable in detecting changes in nutritional and inflammatory parameters over time - combination that may contribute to understanding of its prognostic bearing.