Julie C. Lobo

The newly identified anorexigenic adipokine nesfatin-1 in hemodialysis patients: Are there associations with food intake, body composition and inflammation?

Nesfatin-1 is a recently identified anorexigenic peptide that has been implicated in appetite regulation, weight loss and/or malnutrition. Anorexia and malnutrition are common features of chronic kidney disease (CKD) that predispose patients to worse outcomes. However, the reasons for the occurrence of anorexia in CKD patients are not fully elucidated. The aim of this study was to investigate the association between nesfatin-1 and protein intake and body composition in patients undergoing hemodialysis (HD). Twenty five HD patients from a private Clinic in Rio de Janeiro, Brazil were studied and compared with 15 healthy subjects that were matched for body mass index (BMI), % body fat mass (by anthropometrics) and age. Appetite was measured using a specific questionnaire, and food intake was evaluated based on 3-day food records. Nesfatin-1 levels were measured by ELISA and leptin, TNF-α and IL-6 levels were determined by a multiplex assay kit. Serum nesfatin-1 levels did not differ between HD patients (0.16±0.07ng/mL) and healthy subjects (0.17±0.10ng/mL). Nesfatin-1 levels showed significant negative correlations with protein intake (r=-0.42; p=0.03), but did not associate with inflammatory markers or appetite scores. Combining patients and controls, we observed positive correlations with BMI (r=0.33; p=0.03), % body fat (r=0.35; p=0.03), leptin (r=0.45; p=0.006) and the triceps skinfold thickness (r=0.36; p=0.02). In multivariate analysis % body fat was the main determinant of nesfatin-1 variance. In conclusion, nesfatin-1 levels did not differ between HD patients and healthy subjects and negatively correlated with protein intake. This pathway is likely not dysregulated in uremia.

Is a body mass index of 23 kg/m2 a reliable marker of protein–energy wasting in hemodialysis patients?

OBJECTIVE To evaluate the body composition and inflammatory status in patients on hemodialysis (HD) according to the cutoff of 23 kg/m² for the body mass index (BMI). METHODS Forty-seven patients (30 men, 11 diabetics, 53.8 ± 12.2 y of age, 58.2 ± 50.9 mo on HD) were studied. Anthropometric data and handgrip strength were evaluated. C-reactive protein, tumor necrosis factor-α, leptin, and interleukin-6 were measured. Mortality was assessed after 24 mo of follow-up. RESULTS Nineteen patients (40.4%) presented BMI values lower than 23 kg/m² and leptin levels, midarm muscle area, and free-fat mass were significantly lower in these patients. The prevalence of functional muscle loss according to handgrip strength was not different between the BMI groups. The sum of skinfold thicknesses, the percentage of body fat, fat mass, the fat mass/free-fat mass ratio, and waist circumference were significantly lower in patients with a BMI lower than 23 kg/m², but the mean values did not indicate energy wasting. Patients with a BMI higher than 23 kg/m² presented a higher prevalence of inflammation and higher waist circumference and body fat values. The adiposity parameters were correlated with C-reactive protein and leptin. A Cox multivariate regression analysis demonstrated that C-reactive protein, tumor necrosis factor-α, and interleukin-6 predict cardiovascular mortality. CONCLUSION Patients on HD with a BMI lower than 23 kg/m² did not present signs of energy wasting, whereas those with a BMI higher than 23 kg/m² had more inflammation, probably because of a greater adiposity. Thus, the BMI value of 23 kg/m² does not seem to be a reliable marker of protein-energy wasting in patients on HD.

Is zinc-α2-glycoprotein a cardiovascular protective factor for patients undergoing hemodialysis?

BACKGROUND Zinc-α2-glycoprotein (ZAG) is a lipid mobilizing factor. Its anti-inflammatory action and expression pattern suggest that ZAG could act by protecting against the obesity-associated disorders. In hemodialysis (HD) patients, ZAG levels were described to be elevated but its effects on markers of inflammation and LDL oxidation are still unclear. We investigated the relationship between ZAG and markers of systemic inflammation and LDL atherogenic modification profile in HD patients. METHODS Forty-three patients regularly on HD were studied and compared to 20 healthy subjects. Plasma ZAG, adiponectin, electronegative LDL [LDL(-)], an atherosclerotic negatively charged LDL subfraction, and anti-LDL(-) autoantibodies levels were measured by ELISA. Markers of inflammation and atherogenic cell recruitment (TNF-α, interleukin-6, VCAM-1, ICAM-1, MCP-1 and PAI-1) were also determined. RESULTS Inflammatory markers and atherogenic cell recruitment were higher in HD patients when compared to healthy subjects. ZAG levels were also higher in HD patients (151.5 ± 50.1 mg/l vs 54.6 ± 23.0 mg/l; p<0.0001) and its levels were negatively correlated with TNF-α (r=-0.39; p=0.001) and VCAM-1 (r=-0.52; p<0.0001) and, positively correlated with anti-LDL(-) autoantibodies (r=0.38; p=0.016). On multivariate analyses, plasma ZAG levels were independently associated with VCAM-1 (p=0.01). CONCLUSION ZAG is inversely associated with markers of pro-atherogenic factors linked to systemic inflammation and oxidative stress. Thus, this adipokine may constitute a novel marker of a favorable metabolic profile regarding cardiovascular risk factors in HD population.

Apelin: A Peptide Involved in Cardiovascular Risk in Hemodialysis Patients?

Inflammation, oxidative stress, and obesity are important features associated with pathogenesis of cardiovascular disease, a major contributor to the mortality of hemodialysis (HD) patients. Apelin is an adipokine involved in a variety of physiological functions; however, little is known about apelin in chronic kidney disease (CKD). Thus, the purpose of this study was to analyze apelin plasma levels in HD patients and verify whether there is any relationship with inflammation, oxidative markers, and obesity. Twenty-four HD patients [53.6 ± 14.4 years, 14 men, and body mass index (BMI) of 25.0 ± 4.2 kg/m2] were studied and compared with 15 healthy subjects (51.3 ± 13.5 years, 7 men, and BMI of 26.3 ± 3.7 kg/m2). Plasma apelin-12 and -36 were measured using the enzyme immunometric assay method. Plasma electronegative low-density lipoprotein [LDL(–)] levels were measured using ELISA method, and tumor necrosis factor-α, interleukin-6, leptin, and plasminogen activator inhibitor-1 levels were measured by a multiplex assay kit. C-Reactive protein (CRP) was determined by immunoturbidimetry. Anthropometric data were also evaluated. There was no difference between apelin-36 levels in HD patients (0.82 ± 0.60 ng/mL) and healthy subjects (0.83 ± 0.23 ng/mL). In contrast, apelin-12 levels were significantly higher in patients (0.34 ± 0.15 ng/mL vs. 0.24 ± 0.13 ng/mL in healthy subjects). TNF-α, CRP, and LDL(–) levels were higher in patients; however, there was no correlation among apelin-12 or -36 and inflammatory or oxidative markers. The adiposity parameters were also not associated with apelin-12 or -36. In conclusion, plasma apelin seems to be not associated with cardiovascular risk in HD patients.

Relationship between total ghrelin and inflammation in hemodialysis patients

In hemodialysis (HD) patients studies have shown that plasma ghrelin is increased and it has been speculated that ghrelin levels might be related to systemic inflammation. The present study attempted to correlate the serum levels of total ghrelin with serum TNF-α and IL-6, and with nutritional status and body composition in HD patients. Forty-seven HD patients from a single dialysis unit (18 women, mean age 55.3±12.2 yr; BMI 24.4±4.2kg/m(2); % body fat 29.4±7.4%) were studied and compared to 21 healthy subjects (12 women, 50.7±15.7 yr and BMI 25.6±4.0kg/m(2); % body fat 30.0±5.7%). Biochemical data, serum total ghrelin, TNF-α and IL-6 levels were measured. The body composition was evaluated by dual energy X-ray absortiometry (DEXA) and energy and protein intake were evaluated. Patients showed elevated plasma ghrelin levels when compared to healthy subjects (1.14±1.0ng/mL vs 0.58±0.4; p<0.001). There was a positive correlation between ghrelin levels and TNF-α (r=0.25; p<0.04), IL-6 (r=0.42; p<0.02), and a negative correlation between TNF-α and protein intake (r=-0.28; p<0.03), and energy intake (r=-0.34; p<0.01). No correlation was observed with any aspect of body composition. Plasma ghrelin levels are elevated in HD patients and associated with the state of systemic inflammation. We suggest that the inflammatory state may affect ghrelin bioactivity and metabolism in hemodialysis patients.

Effect of Brazil Nut Supplementation on Plasma Levels of Selenium in Hemodialysis Patients: 12 Months of Follow-up

BACKGROUND Large amounts of reactive oxygen species are produced in hemodialysis (HD) patients, and, at higher concentrations, reactive oxygen species are thought to be involved in the pathogenesis of cardiovascular disease. It has been proposed that selenium (Se) may exert an antiatherogenic influence by reducing oxidative stress. The richest known food source of Se is the Brazil nut (Bertholletia excelsa, family Lecythidaceae), found in the Amazon region. OBJECTIVE The objective of this work was to determine if Se plasma levels in HD patients submitted to a program of supplementation during 3 months with 1 Brazil nut by day could be sustained after 12 months. METHODS A total of 21 HD patients (54.2 ± 15.2 years old; average time on dialysis, 82.3 ± 51.6 months; body mass index, 24.4 ± 3.8 kg/m(2)) from the RenalCor Clinic in Rio de Janeiro, Brazil, were followed up 12 months after the supplementation study ended. The Se plasma levels were determined by atomic absorption spectrophotometry with hydride generation. RESULTS The Se Plasma levels (17.3 ± 19.9 μg/L) were below the normal range (60 to 120 μg/L) before nut supplementation, and after 3 months of supplementation, the levels increased to 106.8 ± 50.3 μg/L (P < .0001). Twelve months after supplementation, the plasma Se levels decreased to 31.9 ± 14.8 μg/L (P < .0001). CONCLUSIONS The data showed that these patients were Se deficient and that the consumption of Brazil nut was effective to increase the Se parameters of nutritional status. Se levels 12 months after the supplementation period were not as low as presupplementation levels but yet significantly lower, and we needed to motivate patients to adopt different dietary intake patterns.

Relationship between zinc levels and plasma leptin in hemodialysis patients

UNLABELLED Recent evidences suggested a possible relationship between zinc deficiency and leptin levels in pathogenesis of anorexia in chronic kidney disease. The present study addressed the relationship between zinc and leptin in hemodialysis (HD) patients. METHODS Fifty HD patients (54.3±12.7years old, 62% men) were studied and compared to 21 healthy volunteers (50.7±15.7years old, 43% men). Biochemical data, serum zinc, plasma leptin, IL-6, TNF-α and C-Reactive Protein levels were determined. Anthropometric parameters, food intake and appetite score were also assessed. RESULTS The leptin levels were higher in HD patients (16.1μg/mL (0.21-118.25) vs 6.0μg/mL (0.50-23.10)) in healthy volunteers (p=0.04), whereas serum zinc levels were lower (54.5±16.3μg/dL) compared to healthy volunteers (78.4±9.4μg/dL) (p=0.0001). The plasma leptin was correlated negatively with plasma zinc (r=-0.33; p=0.007), energy (r=-0.38; p=0.002) and protein intake (r=-0.34; p=0.006) and, positively correlated with BMI (r=0.54; p=0.0001), % body fat (r=0.70; p=0.0001) and conicity index (r=0.46; p=0.001). Plasma zinc was associated with hemoglobin (r=0.30; p=0.04) and negatively associated with TNF-α (r=-0.37; p=0.002) and C-Reactive Protein (r=-0.37; p=0.004). There was no correlation among Zn, leptin and appetite score in these patients. CONCLUSION This study showed that low plasma zinc levels are negatively associated with high leptin levels in HD patients.

Increased electronegative LDL and decreased antibodies against electronegative LDL levels correlate with inflammatory markers and adhesion molecules in hemodialysed patients.

BACKGROUND Chronic Kidney Disease (CKD) patients present high levels of electronegative LDL (LDL-) that can modulate the expression of molecules involved in inflammation and it is closely linked to atherosclerosis. We investigated the association between LDL(-) and inflammatory markers in patients undergoing hemodialysis (HD). METHODS Forty-seven HD patients from a private clinic in Rio de Janeiro, Brazil were studied and compared with 20 age matched healthy individuals. Serum LDL(-) and anti-LDL(-) autoantibody levels were measured by ELISA; TNF-α, IL-6, VCAM-1 and ICAM-1 were determined by a multiplex assay kit. RESULTS HD patients presented higher IL-6 and TNF-α concentrations (4.1 ± 1.6 and 5.5 ± 2.1 pg/ml, respectively) than healthy subjects (2.6 ± 0.2 and 2.4 ± 1.1 pg/ml, respectively) (p=0.0001). In addition, they presented higher VCAM-1 and ICAM-1 levels and, LDL(-) concentrations were also increased (0.18 ± 0.12 U/l) when compared to healthy individuals (0.10 ± 0.08 U/l) (p<0.02). In contrast, the anti-LDL(-) autoantibody levels were lower in HD patients (0.02 ± 0.01 mg/l) than in healthy subjects (0.05 ± 0.03 mg/l) (p<0.001). There was a positive correlation between LDL(-) and IL-6 (r=0.25, p=0.004) and ICAM-1 (r=0.36; p=0.003). There was also a negative correlation between anti-LDL(-) autoantibodies and TNF-α (r=-0.37; p=0.003) and VCAM-1 (r=-0.50; p=0.0001). CONCLUSIONS The association between LDL(-) and inflammation and the lower levels of anti-LDL(-) autoantibodies are important risk factors related to atherosclerosis in CKD.

Reduced Plasma Zinc Levels, Lipid Peroxidation, and Inflammation Biomarkers Levels in Hemodialysis Patients: Implications to Cardiovascular Mortality

Despite the fact that low plasma zinc (Zn) levels play important roles in the oxidative stress, the relationships between lipid peroxidation and inflammation biomarkers with low plasma Zn levels have not been investigated in chronic kidney disease (CKD) patients. The aim of this study was to evaluate the Zn plasma levels, electronegative LDL [LDL(–)] levels, and inflammation markers as predictors of cardiovascular (CV) mortality in hemodialysis (HD) patients. Forty-five HD patients (28 men, 54.2 ± 12.7 years, 62.2 ± 51.4 months on dialysis and BMI 24.3 ± 4.1 kg/m2) were studied and compared to 20 healthy individuals (9 men, 51.6 ± 15.6 years, BMI 25.2 ± 3.9 kg/m2) and followed for 24 months to investigate the risks for CV mortality. LDL(–) levels were measured by ELISA, plasma Zn levels by atomic absorption spectrophotometry, C-reactive protein (CRP) level by immunoturbidimetric method, and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) levels by a multiplex assay kit. HD patients presented low plasma Zn levels (54.9 ± 16.1 μg/dL) and high-LDL(–) (0.18 ± 0.12 U/L) and TNF-α (5.5 ± 2.2 pg/mL) levels when compared to healthy subjects (78.8 ± 9.4μ g/dL, 0.10 ± 0.08U/L, 2.4 ± 1.1 pg/mL, respectively, p < 0.05). Zn plasma levels were negatively correlated to TNF-α (r = –0.49; p = 0.0001) and LDL(–) (r = –0.33; p = 0.008). During the 2 years, 24.4% of the patients died, all due to CV disease. Analysis by the Cox model showed that high CRP, TNF-α, IL-6 levels, and long duration of HD were significant predictors of mortality. In conclusion, reduced Zn levels were associated with lipid peroxidation and inflammation, and we confirm here in a Brazilian cohort of HD patients that inflammation markers are strong predictors of CV death.

The Relationship between Apelin and Parathyroid Hormone in Hemodialysis Patients

Both apelin and parathyroid hormone (PTH) are endogenous ligands for G-protein-coupled receptors. Apelin acts as a mitogenic agent for osteoblasts, and metabolic bone abnormalities are frequently seen in hemodialysis (HD) patients because of hyperparathyroidism. The aim of this study was to analyze plasma apelin levels in HD patients and to determine whether they are related to PTH concentrations. A total of 23 HD patients [15 men and 8 women, with a mean (SD) age of 54.2 (4.4) years and a mean body mass index (BMI) of 25.0 (4.1) kg/m2] were studied and compared with 15 healthy subjects [6 men and 9 women, with a mean (SD) age of 51.3 (13.6) years and a BMI of 27.0 (4.3) kg/m2]. Plasma apelin-36 was measured using an enzyme immunometric assay method and PTH was measured by ELISA. There was no significant difference in apelin levels between the patients [0.80 (0.6) ng/mL] and the healthy subjects [0.83 (0.23) ng/mL]. There was a positive correlation between apelin and PTH (r = 0.66, p = 0.0001). The patients with PTH >300 pg/mL had significantly higher plasma apelin levels [1.17 (0.7) ng/mL] compared with the patients with PTH <300 pg/mL [0.50 (0.15) ng/mL] (p = 0.003). In conclusion, HD patients with secondary hyperparathyroidism have high plasma apelin levels, which suggest that apelin may protect bone in HD patients by acting as an osteoblastic factor.