Background The Malnutrition-Inflammation Score (MIS), a non-expensive and easy-to-assess score between 0 and 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 the MIS risk-stratification of chronic 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 (10/2001–12/2006). Predictors MIS and other nutritional and inflammatory markers. Outcomes & Measurements Prospective all-cause mortality, health-related quality of life via SF-36, and tests of body composition. Results The MIS was correlated with serum interleukin-6 (IL-6) (r=+0.26, p<0.001), C-reactive protein (CRP) (r=+0.16, p<0.001) and several measures of nutritional status. Patients with higher MIS had lower SF-36 scores. After multivariate adjustment for case-mix and other measures of PEW, the chronic HD patients in the second (3–4), third (5–7) and fourth (≥8) quartiles of MIS had worse survival rates than those in the first (0–2) quartile (p<0.001). Each 2 unit increase in MIS was associated with two-fold higher death risk, i.e., adjusted death hazard ratio of 2.03 (95% CI: 1.76–2.33, p<0.001). Cubic spline survival models confirmed linear trends. The areas under the receiver operating characteristic curves for the continuum of MIS in predicting 5-year mortality (0.67) was equal to IL-6 (0.67) and somewhat better than CRP (0.63). Limitations Selection bias and unknown confounders. Conclusions In chronic 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 IL-6 and somewhat greater than CRP. Controlled trials are warranted to examine whether interventions to improve MIS can also improve clinical outcomes in chronic HD 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 Ն120 U/L was associated with a hazard ratio for death of 1.25 (95% confidence interval 1.21 to 1.29; P Ͻ 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 Ͼ120 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. 19: 219319: -220319: , 200819: . doi: 10.1681 In advanced chronic kidney disease (CKD; stages 3 through 5), secondary hyperparathyroidism (SHPT), along with renal osteodystrophy, is common and may be associated with abnormal mineral metabolism and/or abnormal serum or tissue mineral levels, vascular calcifications, and poor survival, espe- contributed to the study design and manuscript preparation and reviewed and approved the final manuscript. J Am Soc Nephrol

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.

Background In maintenance hemodialysis (MHD) patients, a low serum transthyretin (prealbumin) is an indicator of protein-energy wasting. We hypothesized that baseline serum transthyretin correlates independently with health related quality of life (QoL) and death and that its change over time is a robust mortality predictor. Methods Associations and survival predictability of serum transthyretin at baseline and its changes over 6 months were examined in a 5-year (2001-06) cohort of 798 MHD patients. Results Patients with serum transthyretin ≥40 mg/dL had greater mid-arm muscle circumference but lower total body fat percentage. Both serum interleukin-6 and dietary protein intake correlated independently with serum transthyretin. Measures of QoL indicated better physical health, physical function and functionality in higher transthyretin levels. Although baseline transthyretin was not superior to albumin in predicting survival, in both all and normoalbuminemic (albumin≥3.5 g/dL, n=655) patients, transthyretin<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 transthyretin between 20 and 40 mg/dl, whose serum transthyretin was remeasured after 6 months, a 10 mg/dL or greater fall resulted in death hazard ratio of 1.37 (95% confidence levels: 1.02, 1.85; p=0.03) after adjustment for baseline measures including inflammatory markers. Conclusions Even though baseline serum transthyretin may not be superior to albumin in predicting mortality in MHD patients, transthyretin levels below 20 mg/dL are associated with death risk even in normoalbuminemic patients, and a fall in serum transthyretin over 6 months is independently associated with increased death risk.

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 >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 >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 >500 ng/ml and ISAT <25% had higher odds ratio for serum C-reactive protein >10 mg/L. The area under the receiver operating characteristic curves for the continuum of ISAT and IL-6 in detecting a serum ferritin >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.

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.

Background The 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 (mCD14) forms. The correlates of sCD14 in persons undergoing long-term hemodialysis (HD) are not known. Study Design We hypothesized that elevated sCD14 in hemodialysis patients is associated pro-inflammatory cytokine activation and increased mortality in a 33-month cohort Subjects Well defined cohort of 310 long-term HD patients who participated in the Nutritional and Inflammatory Evaluation in Dialysis (NIED) Study. Predictors and other Measurements Soluble CD14 in serum. Predictors and other Measurements Thirty-three month mortality in the NIED Study cohort. Results The mean sCD14 was 7.24±2.45 μg/ml. Tumor necrosis factor-α (TNF-α) was the strongest correlate of sCD14 (r=+0.24, p<0.001) followed by interleukin(IL)-6 (r=+0.18, p=0.002), serum ferritin (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-C (r=+0.13, p=0.03) and body fat (r=−0.11, p=0.06). Over the 33 months follow-up, 71 (23%) patients died. Multivariable Cox proportional analysis adjusted for case-mix and other nutritional and inflammatory confounders including serum TNF-α, C-Reactive protein, and IL-6 showed that compared to lowest sCD14 tertile, sCD14 levels in the third tertile (>7.8 μg/ml) were associated with higher death risk (hazard ratio, 1.94; 95% confidence interval, 1.01–3.75, p=0.04). Limitations Survivor bias in combined incident/prevalent studies. Conclusions Elevated sCD14 is positively related to markers of inflammation, negatively related to nutritional status and an independent predictor of mortality in long-term HD patients. Further studies are needed to examine the usefulness of sCD14 in risk stratification and clinical decision-making process in 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, Q(25-75): 81-141); 36% had AlkPhos>/=120 U/L and 50% had a total T-score< or =-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> or =120 U/L compared with <120 U/L (1.01 +/- 0.016 vs. 1.08 +/- 0.013 g/cm(2), respectively, P<0.001). The multivariate adjusted odds ratio of AlkPhos> or =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> or =120 U/L was a better predictor of total T-score< or =-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..