Nutritional and Inflammatory Aspects of Low Parathyroid Hormone in Maintenance Hemodialysis Patients-A Longitudinal Study.

BACKGROUND: Low serum parathyroid hormone (PTH) is an accepted marker for adynamic bone disease which is characterized by increased morbidity and mortality in maintenance hemodialysis (MHD) patients. In light of the known cross-sectional associations between PTH and malnutrition-inflammation syndrome, we aimed to examine the longitudinal associations between PTH with changes in nutritional and inflammatory parameters and clinical outcomes in MHD patients with low PTH. METHODS: This historical prospective and longitudinal study analyzed a clinical database at a single hemodialysis center, containing the medical records of 459 MHD patients (mean age of 71.4 ± 12.9 years old, 171 women), treated between the years 2007-2020. Bone turnover, nutritional and inflammatory marker levels were recorded at 0, 6, 12, 18, 24, 30, and 36 months followed by a median of 24 additional months of clinical observations. According to previous use of vitamin D analogs and/or calcium-sensing receptor agonists, the study participants were divided into treatment-related and disease-related groups. A linear mixed effects model was adjusted for baseline demographics and clinical parameters. RESULTS: Of 459 MHD patients, 81 (17.6%) had PTH lower than 150pg/mL. Among them, 30 patients had treatment-related and 51 had disease-related low PTH. At baseline, MHD patients with treatment-related low PTH had a higher rate of diabetes compared to the disease-related group. In a linear mixed effects model, increased PTH over time was associated with decreased levels of alkaline phosphatase and C-reactive protein and with increased hemoglobin and albumin, but not the geriatric nutritional risk index at 3-year follow-up. The survival rate did not differ between the groups, with the risk of hospitalizations due to fractures being higher (HR: 4.04 with 95% CI: 1.51-10.8) in the disease-related group. Statistical significance of this association was abolished after adding C-reactive protein or alkaline phosphatase to the multivariate models. CONCLUSIONS: Low serum PTH in MHD patients behaves differently depending on its cause, with a higher risk of fractures in the disease-related group. This association is dependent on inflammation. Our results should be verified in larger epidemiological studies.

Sarcopenic Obesity Versus Nonobese Sarcopenia in Hemodialysis Patients: Differences in Nutritional Status, Quality of Life, and Clinical Outcomes.

OBJECTIVE: Sarcopenia and sarcopenic obesity (SO) are linked to unfavorable prognosis in maintenance hemodialysis (MHD) populations. We tested whether nonobese sarcopenia and SO, as different stages of extreme protein-energy wasting, have different prognoses. METHODS: In this prospective observational study, 261 MHD patients were recruited from October 2010 to April 2012 and followed until October 2020. Two definitions were used to diagnose sarcopenia: the European Working Group on Sarcopenia in Older People consensus and the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium criteria. Obesity was determined as the percentage of total body fat, ≥27% for men and ≥38% for women. Data for all-cause and cardiovascular morbidity and mortality, baseline nutrition markers, inflammation and oxidative stress, adipokines, body composition parameters, handgrip strength, and quality of life (QoL) scores were measured. RESULTS: According to European Working Group on Sarcopenia in Older People, 115 (44.1%) patients were sarcopenic and 120 (46.0%) according to FNIH definitions. Of them, 28.4% and 34.5% were SO, respectively. Higher levels of albumin, creatinine, uric acid, leptin, phase angle, better nutritional scores, and lower adiponectin levels characterized SO patients compared with nonobese sarcopenic patients regardless of indexing method. Better QoL scores were noted in SO compared with nonobese sarcopenic patients using the FNIH sarcopenia criteria. The hazard of all-cause death, cardiovascular death, and first cardiovascular event for patients with SO was lower compared with the nonobese patients after multivariate adjustments. Statistical significance of these associations disappeared after including fat mass in multivariate models. CONCLUSIONS: MHD patients with SO have better nutritional status and prognosis for cardiovascular events, all-cause and cardiovascular disease mortality, and possibly better QoL compared with nonobese sarcopenic MHD patients. The better prognosis appears to be entirely due to the excess fat, which is protective in sarcopenic MHD patients similar to that described in the entire MHD population.

Usual nutritional scores have acceptable sensitivity and specificity for diagnosing malnutrition compared to GLIM criteria in hemodialysis patients.

Diagnosing malnutrition by the recently published Global Leadership Initiative on Malnutrition (GLIM) criteria requires using modern techniques for body composition measurements. We hypothesized that the prevalence of malnutrition identified by usual nutritional scores and according to GLIM criteria may be close to each other due to the number of components shared between them. Our aim was to compare the concurrent validity of four nutritional scores, malnutrition-inflammation score (MIS), objective score of nutrition on dialysis, geriatric nutritional index (GNRI), and nutritional risk index against the GLIM criteria for malnutrition in maintenance hemodialysis patients. This prospective observational study was performed on 318 maintenance hemodialysis outpatients (37% women) with a mean age of 68.7 ± 13.1 years and a median dialysis vintage of 21 months. According to the GLIM criteria, 45.9% of these patients were diagnosed with malnutrition. Nutritional scores, dietary intake and body composition parameters were measured. All nutritional scores showed a strong association with malnutrition in multivariable logistic regression models. In discriminating the nutritional risk, the ROC AUC was largest for GNRI (0.70, 95% CI: 0.65-0.75; P< .001). Nutritional risk index and MIS showed high specificity but lower sensitivity compared to GNRI and objective score of nutrition on dialysis. Compared to MIS, GNRI had better concurrent validity (higher sensitivity and acceptable specificity) but was inferior to MIS in terms of relation to certain etiologic and phenotypic components of the GLIM criteria (specifically, to dietary intake and decrease in dry weight). In summary, of the nutritional scores tested, GNRI is the most sensitive score in identifying malnutrition diagnosed by GLIM criteria, but MIS is more specific and better in predicting the individual components of the GLIM criteria.

Comorbidity burden may explain adiponectin's paradox as a marker of increased mortality risk in hemodialysis patients.

Despite experimental evidence of beneficial metabolic, antiatherosclerotic and antiinflammatory effects of the 30 kDa adipokine, adiponectin, maintenance hemodialysis (MHD) patients with high adiponectin blood levels have paradoxically high mortality rates. We aimed to examine the direction of the associations between adiponectin and all-cause and cardiovascular mortality as well as with markers of oxidative stress, inflammation and nutrition in MHD patients with varying degrees of comorbidities. A cohort of 261 MHD patients (mean age 68.6 ± 13.6 years, 38.7% women), grouped according to baseline comorbidity index (CI) and serum adiponectin levels, were followed prospectively for six years. High and low concentrations were established according to median CI and adiponectin levels and cross-classified. Across the four CI-adiponectin categories, the group with low comorbidities and high adiponectin exhibited the best outcomes. Conversely, the high comorbidity group with high adiponectin levels had the lowest survival rate in both all-cause mortality (log rankχ2 = 23.74, p < 0.001) and cardiovascular mortality (log rankχ2 = 34.16, p < 0.001). Further data adjustment for case-mix covariates including fat mass index did not substantially affect these results. In conclusion, the direction of adiponectin's prognostic associations in MHD patients is inverse in those with few comorbidities and direct in those with many comorbidities.

Biological basis of lymphocyte ratios for survival prediction in hemodialysis patients: a longitudinal study.

PURPOSE: The neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios have been proposed as emerging markers of inflammation and prognosis in maintenance hemodialysis (MHD) patients. However, to date, no longitudinal performance of these indices is known. The study's purpose was to examine the longitudinal relationship between NLR, PLR, inflammatory and nutritional parameters in MHD patients and how their changes over time associate with adverse clinical outcomes. METHODS: A historical longitudinal cohort study was conducted using a clinical database which included 554 patients (mean age, 67.6 ± 14.2 years; 34% women) from a single center receiving MHD from November 2007 to July 2018. NLR, PLR, C-reactive protein (CRP) and nutritional parameters were recorded at 0, 6, 12, 18, 24, 30 and 36 months, followed by 58 additional months of clinical observations. RESULTS: In a linear mixed-effects model adjusted for baseline demographics and clinical parameters, including white blood cell count, NLR and PLR were both associated with CRP levels at any given time point observation (linear estimates (95% CI): 1.53, (0.11-2.95) and 1.55 (0.15-2.93), respectively). For each 1.0-unit increase in NLR over time, the fully adjusted all-cause mortality hazard ratio using Cox models with the time-varying risk effect was 1.04 (95% CI 1.01-1.07, P = 0.006). However, when CRP was included in this model, the relationship was no longer significant. PLR's performance did not match the prognostic marker. CONCLUSION: Longitudinal changes in NLR mimic CRP changes and predict all-cause mortality risk in MHD patients.

Obestatin levels in response to a meal and association with subsequent appetite sensations in maintenance hemodialysis patients.

BACKGROUND: Obestatin, a physiological opponent of acylated ghrelin, is linked to appetite suppression regulation in mice but its anorexigenic properties in humans are controversial. We aimed to investigate obestatin's potential role in dietary intake regulation by examining response to a meal in maintenance hemodialysis (MHD) patients. METHODS: In this prospective observational case series study, we investigated the response of obestatin to a fixed calorie meal (500 kcal) in 21 MHD patients (age 69.2 ± 13.1 years, 10 women, with a body mass index 27.2 ± 5.5 kg/m2). Parallel changes in serum obestatin and insulin levels and subjective scores of appetite (visual analogue scales for hunger, satiety, fullness and prospective food consumption) were recorded on fasting and 30, 60 and 120 min after the meal. RESULTS: In a linear mixed effects model controlling for baseline demographics and clinical parameters including serum insulin concentrations, postprandial levels of obestatin did not change significantly from baseline in response to the meal. The response was the same in MHD patients treated with high- or low-flux dialyzers. However, postprandial obestatin levels were associated with the rate of change in sensation of fullness (linear estimate: 11.60 (95% confidence interval 0.17 to 23.04, P < 0.05)). The remaining sensations of appetite did not correlate with postprandial obestatin levels in time. CONCLUSIONS: Obestatin levels do not change acutely with food administration in MHD patients, but associate with the changes in sensation of fullness. This supports the possible role of obestatin in the long-term regulation of appetite in MHD patients.

Nutritional Status and Mortality Predictability for Time-Varying Serum Alkaline Phosphatase in Hemodialysis Patients: A Longitudinal Study.

OBJECTIVE: Higher serum alkaline phosphatase (sALP) levels associate with a poor prognosis in maintenance hemodialysis patients. However, little is known about the meaning of lower sALP in this population. We hypothesized that lower sALP concentrations may express nutritional status and survival accordingly. METHODS: A retrospective, longitudinal cohort study of a clinical database containing the medical records of 554 patients (367 men and 187 women, mean age 67.6 ± 14.2 years) receiving maintenance hemodialysis from November 2007 to July 2018 in a single center was conducted. sALP, nutritional, bone turnover, and inflammatory marker levels were recorded at 0, 6, 12, 18, 24, 30,and 36 months followed by 58 additional months of clinical observations. RESULTS: The median sALP level was 90.0 (71.0-125.8) U/L. In a linear mixed effects model adjusted for baseline demographics and clinical parameters, each 1.0 U/L increase above the mean sALP at baseline was associated with 0.7% slower rate of decline in geriatric nutritional risk index per 3 years (P = .02 for sALP × time interaction). sALP remained associated with the rate of change in geriatric nutritional risk index, even after controlling for C-reactive protein and intact parathyroid hormone levels. For each 1.0 U/L increase in sALP over time, the fully adjusted all-cause mortality hazard ratio using Cox models with the time-varying risk effect was 0.996 (95% confidence interval 0.993-1.000, P = .04). CONCLUSIONS: Increasing longitudinal levels of sALP associate with improved nutritional status and lower mortality rates. sALP can be used as an integrated marker, combining the properties of the nutritional marker, the marker of mineral-bone disease and inflammation, according to its levels.

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.

Phosphate binders, appetite and nutritional status in maintenance hemodialysis patients.

BACKGROUND AND OBJECTIVES: The potential side effects of common phosphate binders are gastrointestinal in practice. We hypothesized that regular use of phosphate binders may be associated with decreased appetite, dietary intake and consequently, poor nutritional status. METHODS AND STUDY DESIGN: This was cross-sectional study of 78 patients (mean age 67.5±13.0, 34.6% women) undergoing maintenance hemodialysis (MHD) treatment. Participants were divided into three equal groups - sevelamer (n=25), lanthanum (n=24) and the control group (n=29). Eating motivation was assessed using visual analogue scales (VAS) and by a self-reported appetite assessment which was graded on a 5-point Likert scale. Main outcome measure was differences in VAS scores for appetite, dietary intake and nutritional status (malnutrition-inflammation score [MIS]) in the study groups. RESULTS: Appetite, dietary intake, biochemical nutritional markers, anthropometric measures and MIS were similar in the three groups. A statistically significant difference was observed in sensation of fullness between the groups: multivariable adjusted ORs in the sevelamer carbonate group was 4.90 (95% CI: 1.12 to 21.43), p=0.04 and in the lanthanum carbonate group was 5.18 (95% CI: 1.15 to 23.30), p=0.03 versus the control group. However, no linear association was observed between MIS scores and VAS scores for appetite in any study group. CONCLUSIONS: Regular use of these phosphate binders was not associated with anorexia, decreased dietary intake and nutritional status in the study population. Therefore, there is no preference in the choice of phosphate binders in MHD patients with hyperphosphatemia, even those who are at nutritional risk.

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/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.

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.

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.

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.

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.

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.

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.