Mehdi Rambod

Association of Malnutrition-Inflammation Score With Quality of Life and Mortality in Hemodialysis Patients: A 5-Year Prospective Cohort Study

BACKGROUND The Malnutrition-Inflammation Score (MIS), an inexpensive and easy-to-assess score of 0 to 30 to examine protein-energy wasting (PEW) and inflammation, includes 7 components of the Subjective Global Assessment, body mass index, and serum albumin and transferrin concentrations. We hypothesized that MIS risk stratification of hemodialysis (HD) patients in predicting outcomes is better than its components or laboratory markers of inflammation. STUDY DESIGN 5-Year cohort study. SETTING & PARTICIPANTS We examined 809 stable HD outpatients and followed them for up to 5 years (October 2001 to December 2006). PREDICTORS MIS and other nutritional and inflammatory markers. OUTCOMES & MEASUREMENTS Prospective all-cause mortality, health-related quality of life using the 36-Item Short Form Health Survey (SF-36), and tests of body composition. RESULTS The MIS correlated with logarithm of serum interleukin 6 level (r = +0.26; P < 0.001), logarithm of C-reactive protein level (r = +0.16; P < 0.001), and several measures of nutritional status. Patients with a higher MIS had lower SF-36 scores. After multivariate adjustment for case-mix and other measures of PEW, HD patients in the second (3 to 4), third (5 to 7), and fourth (>or=8) quartiles of MIS had worse survival rates than those in the first (0 to 2) quartile (P < 0.001). Each 2-unit increase in MIS was associated with a 2-fold greater death risk, ie, adjusted death hazard ratio of 2.03 (95% confidence interval, 1.76 to 2.33; P < 0.001). Cubic spline survival models confirmed linear trends. Adding MIS to the constellation of age, sex, race/ethnicity, and vintage significantly improved the area under the receiver operating characteristic curve developed for predicting mortality (0.71 versus 0.67; P < 0.001). LIMITATIONS Selection bias and unknown confounders. CONCLUSIONS In HD patients, the MIS is associated with inflammation, nutritional status, quality of life, and 5-year prospective mortality. The mortality predictability of the MIS appears equal to serum interleukin 6 and somewhat greater than C-reactive protein levels. Controlled trials are warranted to examine whether interventions to improve the MIS can also improve clinical outcomes in HD patients.

Serum Alkaline Phosphatase Predicts Mortality among Maintenance Hemodialysis Patients

Several observational studies have demonstrated that serum levels of minerals and parathyroid hormone (PTH) have U- or J-shaped associations with mortality in maintenance hemodialysis patients, but the relationship between serum alkaline phosphatase (AlkPhos) and risk for all-cause or cardiovascular death is unknown. In this study, a 3-yr cohort of 73,960 hemodialysis patients in DaVita outpatient dialysis were studied, and the hazard ratios for all-cause and cardiovascular death were higher across 20-U/L increments of AlkPhos, including within the various strata of intact PTH and serum aspartate aminotransferase. In the fully adjusted model, which accounted for demographics, comorbidity, surrogates of malnutrition and inflammation, minerals, PTH, and aspartate aminotransferase, AlkPhos > or =120 U/L was associated with a hazard ratio for death of 1.25 (95% confidence interval 1.21 to 1.29; P < 0.001). This association remained among diverse subgroups of hemodialysis patients, including those positive for hepatitis C antibody. A rise in AlkPhos by 10 U/L during the first 6 mo was incrementally associated with increased risk for death during the subsequent 2.5 yr. In summary, high levels of serum AlkPhos, especially >120 U/L, are associated with mortality among hemodialysis patients. Prospective controlled trials will be necessary to test whether serum AlkPhos measurements could be used to improve the management of renal osteodystrophy.

Association of serum prealbumin and its changes over time with clinical outcomes and survival in patients receiving hemodialysis

BACKGROUND In patients receiving maintenance hemodialysis (MHD), a low serum prealbumin is an indicator of protein-energy wasting. OBJECTIVE We hypothesized that baseline serum prealbumin correlates independently with health-related quality of life (QoL) and death and that its change over time is a robust mortality predictor. DESIGN Associations and survival predictability of serum prealbumin at baseline and its changes over 6 mo were examined in a 5-y (2001-2006) cohort of 798 patients receiving MHD. RESULTS Patients with serum prealbumin >or= 40 mg/dL had greater mid-arm muscle circumference but lower percentage of total body fat. Both serum interleukin-6 and dietary protein intake correlated independently with serum prealbumin. Measures of QoL indicated better physical health, physical function, and functionality with higher prealbumin concentrations. Although baseline prealbumin was not superior to albumin in predicting survival, in both all and normoalbuminemic (albumin >or= 3.5 g/dL; n = 655) patients, prealbumin < 20 mg/dL was associated with higher death risk in adjusted models, but further adjustments for inflammatory cytokines mitigated the associations. In 412 patients with baseline prealbumin between 20 and 40 mg/dL whose serum prealbumin was remeasured after 6 mo, a >or=10-mg/dL fall resulted in a death hazard ratio of 1.37 (95% CI: 1.02, 1.85; P = 0.03) after adjustment for baseline measures, including inflammatory markers. CONCLUSIONS Even though baseline serum prealbumin may not be superior to albumin in predicting mortality in MHD patients, prealbumin concentrations <20 mg/dL are associated with death risk even in normoalbuminemic patients, and a fall in serum prealbumin over 6 mo is independently associated with increased death risk.

Association of Serum Alkaline Phosphatase with Coronary Artery Calcification in Maintenance Hemodialysis Patients

BACKGROUND AND OBJECTIVES Recent in vitro studies have shown a link between alkaline phosphatase and vascular calcification in patients with chronic kidney disease (CKD). High serum levels of alkaline phosphatase are associated with increased death risk in epidemiologic studies of maintenance hemodialysis (MHD) patients. We hypothesized that coronary artery calcification is independently associated with increased serum alkaline phosphatase levels in MHD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We examined the association of coronary artery calcification score (CACS) and alkaline phosphatase in 137 randomly selected MHD patients for whom markers of malnutrition, inflammation, and bone and mineral disorders were also measured. RESULTS Serum alkaline phosphatase was the only measure with significant and robust association with CACS (P < 0.003), whereas either other biochemical markers had no association with CACS or their association was eliminated after controlling for case-mix variables. Serum alkaline phosphatase >120 IU/L was a robust predictor of higher CACS and was particularly associated with the likelihood of CACS >400 (multivariate odds ratio 5.0 95% confidence interval 1.6 to 16.3; P = 0.007). Serum alkaline phosphatase of approximately 85 IU/L seemed to be associated with the lowest likelihood of severe coronary artery calcification, but in the lowest tertile of alkaline phosphatase, the CACS predictability was not statistically significant. CONCLUSIONS An association between serum alkaline phosphatase level and CACS exists in MHD patients. Given the high burden of vascular calcification in patients with CKD, examining potential therapeutic interventions to modulate the alkaline phosphatase pathway may be warranted.

Combined High Serum Ferritin and Low Iron Saturation in Hemodialysis Patients: The Role of Inflammation

BACKGROUND Serum ferritin, frequently used as a marker of iron status in individuals with chronic kidney disease, is also an inflammatory marker. The concurrent combination of high serum ferritin and low iron saturation ratio (ISAT) usually poses a diagnostic dilemma. We hypothesized that serum ferritin > or =500 ng/ml, especially in the seemingly paradoxical presence of ISAT level <25%, is more strongly associated with inflammation than with iron in maintenance hemodialysis (MHD) patients. DESIGN, SETTING, AND PARTICIPANTS In 789 MHD patients in the Los Angeles area, the association of serum ferritin > or =500 ng/ml with inflammatory markers, including IL-6 (IL-6) and C-reactive protein levels, and malnutrition-inflammation score (MIS) was examined. RESULTS After multivariate adjustment for case-mix and other measures of malnutrition-inflammation complex, MHD patients with serum ferritin > or =500 ng/ml and ISAT <25% had higher odds ratio for serum C-reactive protein > or =10 mg/L. The area under the receiver operating characteristic curves for the continuum of ISAT and IL-6 in detecting a serum ferritin > or =500 ng/ml were identical (0.57 versus 0.56, P = 0.7). The combination of IL-6 with ISAT yielded a higher area under the receiver operating characteristic curve (0.61) than either ISAT or IL-6 alone (P = 0.03 and P = 0.02, respectively). CONCLUSION In MHD patients, ferritin values above 500 ng/ml, especially in paradoxical conjunction with low ISAT, are associated with inflammation. Strategies to dissociate inflammation from iron metabolism to mitigate the confounding impact of inflammation on iron and to improve iron treatment responsiveness may improve anemia management in chronic kidney disease.

Association of Soluble Endotoxin Receptor CD14 and Mortality Among Patients Undergoing Hemodialysis

BACKGROUND CD14 is a key molecule in innate immunity that mediates cell activation and signaling in response to endotoxin and other bacterial wall-derived components. CD14 protein exists in soluble (sCD14) and membrane-bound forms. The correlates of sCD14 in persons undergoing long-term hemodialysis (HD) therapy are not known. We hypothesized that increased sCD14 levels in HD patients are associated with proinflammatory cytokine activation and increased mortality. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS 310 long-term HD patients who participated in the Nutritional and Inflammatory Evaluation in Dialysis (NIED) Study, a cohort derived from a pool of more than 3,000 HD outpatients during 5 years in 8 DaVita maintenance dialysis facilities in the South Bay Los Angeles, CA, area. PREDICTORS sCD14 levels in serum. OUTCOMES 33-month mortality. RESULTS Mean sCD14 level was 7.24 +/- 2.45 microg/mL. Tumor necrosis factor alpha level was the strongest correlate of sCD14 level (r = +0.24; P < 0.001), followed by interleukin 6 level (r = +0.18; P = 0.002), serum ferritin level (r = +0.21; P < 0.001), total iron-binding capacity (r = -0.19; P < 0.001), body mass index (r = -0.15; P = 0.008), vintage (r = +0.14; P = 0.01), low-density lipoprotein cholesterol level (r = +0.13; P = 0.03), and body fat (r = -0.11; P = 0.06). During the 33-month follow-up, 71 (23%) patients died. Multivariable Cox proportional analysis adjusted for case-mix and other nutritional and inflammatory confounders, including serum tumor necrosis factor alpha, C-reactive protein, and interleukin 6 levels, showed that compared with the lowest sCD14 tertile, sCD14 levels in the third tertile (>7.8 microg/mL) were associated with greater death risk (hazard ratio, 1.94; 95% confidence interval, 1.01 to 3.75; P = 0.04). LIMITATIONS Survivor bias in combined incident/prevalent studies. CONCLUSIONS Increased sCD14 level is related positively to markers of inflammation and negatively to nutritional status and is an independent predictor of mortality in long-term HD patients. Additional studies are needed to examine the usefulness of sCD14 level in risk stratification and the clinical decision-making process in HD patients.

Association of Serum Total Iron-Binding Capacity and Its Changes Over Time with Nutritional and Clinical Outcomes in Hemodialysis Patients

Serum transferrin, estimated by total iron-binding capacity (TIBC), may be a marker of protein-energy wasting (PEW) in maintenance hemodialysis (MHD) patients. We hypothesized that low TIBC or its fall over time is associated with poor clinical outcomes. In 807 MHD patients in a prospective 5-year cohort, associations of TIBC and its changes over time with outcomes were examined after adjustment for case-mix and markers of iron stores and malnutrition-inflammation including serum interleukin-6, iron and ferritin. Patients with serum TIBC ≥250 mg/dl had higher body mass index, triceps and biceps skinfolds and mid-arm muscle circumference and higher serum levels of iron but lower ferritin and inflammatory markers. Some SF-36 quality of life (QoL) components were worse in the lowest and/or highest TIBC groups. Mortality was incrementally higher in lower TIBC levels (p-trend <0.001). Adjusted death hazard ratio was 1.75 (95% CI: 1.00–3.05, p = 0.05) for TIBC <150 compared to TIBC of 200–250 mg/dl. A fall in TIBC >20 mg/dl over 6 months was associated with a death hazard ratio of 1.57 (95% CI: 1.04–2.36, p = 0.03) compared to the stable TIBC group. Hence, low baseline serum TIBC is associated with iron deficiency, PEW, inflammation, poor QoL and mortality, and its decline over time is independently associated with increased death risk.

Association of serum alkaline phosphatase and bone mineral density in maintenance hemodialysis patients.

Recent studies indicate that serum alkaline phosphatase (AlkPhos), a surrogate of high turnover bone disease, is associated with coronary artery calcification and death risk in maintenance hemodialysis (MHD) patients. The association between AlkPhos and bone mineral density (BMD) is not well studied. We studied the association between AlkPhos and dual‐energy X‐ray absorptiometry‐assessed BMD in a group of MHD patients in Southern California. In 154 MHD patients, aged 55.3 ± 13.6 years, including 42% women, 38% Hispanics, 42% African Americans, and 55% diabetics, the mean serum AlkPhos was 121 ± 63 U/L (median: 101, Q25–75: 81–141); 36% had AlkPhos≥120 U/L and 50% had a total T‐score≤−1. Whereas the total BMD did not correlate with age (r=0.01, P=0.99) or body mass index (r=0.10, P=0.22), it correlated negatively with AlkPhos (r=−0.25, P=0.002), including after multivariate adjustment (r=−0.24, P=0.003). The proportion of patients with a high coronary artery calcification score>400 was incrementally higher across worsening BMD tertiles (P trend=0.04). The BMD was significantly worse in MHD patients with serum AlkPhos≥120 U/L compared with <120 U/L (1.01 ± 0.016 vs. 1.08 ± 0.013 g/cm2, respectively, P<0.001). The multivariate adjusted odds ratio of AlkPhos≥120 U/L for having a total T‐score<−1.0 was 2.3 (1.1–4.8, P=0.037). Among routine clinical and biochemical markers, serum AlkPhos≥120 U/L was a better predictor of total T‐score≤−1 in MHD patients. An association exists between higher serum AlkPhos and worse dual‐energy X‐ray absorptiometry‐assessed BMD in MHD patients. Given these findings, studies are indicated to examine whether interventions that lower serum AlkPhos improve BMD in MHD patients.

Six-minute walk distance predictors, including CT scan measures, in the COPDGene cohort.

BACKGROUND Exercise tolerance in COPD is only moderately well predicted by airflow obstruction assessed by FEV(1). We determined whether other phenotypic characteristics, including CT scan measures, are independent predictors of 6-min walk distance (6MWD) in the COPDGene cohort. METHODS COPDGene recruits non-Hispanic Caucasian and African American current and ex-smokers. Phenotyping measures include postbronchodilator FEV(1) % predicted and inspiratory and expiratory CT lung scans. We defined % emphysema as the percentage of lung voxels < -950 Hounsfield units on the inspiratory scan and % gas trapping as the percentage of lung voxels < -856 Hounsfield units on the expiratory scan. RESULTS Data of the first 2,500 participants of the COPDGene cohort were analyzed. Participant age was 61 ± 9 years; 51% were men; 76% were non-Hispanic Caucasians, and 24% were African Americans. Fifty-six percent had spirometrically defined COPD, with 9.3%, 23.4%, 15.0%, and 8.3% in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I to IV, respectively. Higher % emphysema and % gas trapping predicted lower 6MWD (P < .001). However, in a given spirometric group, after adjustment for age, sex, race, and BMI, neither % emphysema nor % gas trapping, or their interactions with FEV(1) % predicted, remained a significant 6MWD predictor. In a given spirometric group, only 16% to 27% of the variance in 6MWD could be explained by age, male sex, Caucasian race, and lower BMI as significant predictors of higher 6MWD. CONCLUSIONS In this large cohort of smokers in a given spirometric stage, phenotypic characteristics were only modestly predictive of 6MWD. CT scan measures of emphysema and gas trapping were not predictive of 6MWD after adjustment for other phenotypic characteristics.

Testosterone and resistance training effects on muscle nitric oxide synthase isoforms in COPD men

BACKGROUND Skeletal muscle dysfunction contributes to exercise limitation in COPD. The role of the nitric oxide synthase (NOS) system in muscle dysfunction is ill defined. Reduced levels of endothelial NOS (eNOS) and elevated levels of inducible NOS (iNOS) in the skeletal muscle of COPD patients have been recently reported. We hypothesized that resistance exercise training (R) and/or testosterone supplementation (T) would alter the transcription and expression of the NOS isoenzymes in COPD skeletal muscle. METHODS Vastus lateralis biopsies were obtained before and after a 10-week intervention in 40 men with severe COPD(age 67.7 ± 8.3, FEV(1) 41.4 ± 12.6% predicted): placebo + no training (P) (n = 11), placebo + resistance training (PR) (n = 8), testosterone + no training (T) (n = 11) and testosterone + resistance training (TR) (n = 10) groups. eNOS, nNOS and iNOS mRNA and protein levels were measured in each sample. mRNA and protein levels were measured using real-time PCR and enzyme-linked immunosorbant assay, respectively. RESULTS eNOS mRNA increased in the TR group compared to P and T groups (P < 0.001). eNOS protein was increased in TR and T groups after intervention (P < 0.05) but not in the PR group. nNOS protein increased in the PR, T, and TR groups (P < 0.05). iNOS protein decreased only in the TR group (P = 0.01). CONCLUSION Resistance training and testosterone supplementation increased eNOS and nNOS proteins and decreased iNOS protein in the skeletal muscles of men with COPD. These changes in NO system might explain some of the favorable effects of these therapies.