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BACKGROUND. Systemic inflammation and muscle wasting are highly prevalent and coexist in patients on maintenance hemodialysis (MHD). We aimed to determine the effects of systemic inflammation on skeletal muscle protein metabolism in MHD patients. METHODS. Whole body and skeletal muscle protein turnover were assessed by stable isotope kinetic studies. We incorporated expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue from integrin β1 gene KO CKD mice models. RESULTS. Among 129 patients with mean (± SD) age 47 ± 12 years, 74% were African American, 73% were male, and 22% had diabetes mellitus. Median high-sensitivity C-reactive protein (hs-CRP) concentration was 13 (interquartile range 0.8, 33) mg/l. There were statistically significant associations between hs-CRP and forearm skeletal muscle protein synthesis, degradation, and net forearm skeletal muscle protein balance (P < 0.001 for all). The associations remained statistically significant after adjustment for clinical and demographic confounders, as well as in sensitivity analysis, excluding patients with diabetes mellitus. In attempting to identify potential mechanisms involved in this correlation, we show increased expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue obtained from an animal model of chronic kidney disease. CONCLUSION. These data suggest that systemic inflammation is a strong and independent determinant of skeletal muscle protein homeostasis in MHD patients, providing rationale for further studies using anticytokine therapies in patients with underlying systemic inflammation. FUNDING. This study was in part supported by NIH grants R01 DK45604 and 1K24 DK62849, the Clinical Translational Science Award UL1-TR000445 from the National Center for Advancing Translational Sciences, the Veterans Administration Merit Award I01 {"type":"entrez-nucleotide","attrs":{"text":"CX000414","term_id":"56271831","term_text":"CX000414"}}CX000414, the SatelliteHealth Normon Coplon Extramural Grant Program, and the FDA grant 000943.

Objective Sarcopenic obesity (SO), a combination of low muscle mass and high fat mass, is considered as risk factor for mortality in general population. It is unclear if SO affects mortality in maintenance hemodialysis (MHD) patients. In this study, we aimed to determine whether body composition as assessed by currently available SO definitions is related to all-cause mortality in MHD subjects. We also examined the impact of applying different definitions on the prevalence of SO in our MHD database. Design Retrospective analysis. Subjects Adult patients on MHD for at least 3 months with no acute illness studied in the clinical research center between 2003 and 2011. Intervention Assessment of body composition was performed using dual energy x-ray absorptiometry. SO (appendicular skeletal mass: arm lean mass + leg lean mass and fat mass) was defined according to Baumgartner definition, Janssen criteria 1, and Janssen criteria 2. Main Outcome Measure All-cause mortality and prevalence of SO. Patient deaths were ascertained from medical records and United States social security death index. Results Of 122 participants, 62% were male; mean age was 46 years (interquartile range: 40, 54) in men and 50 years (44, 61) in women. Prevalence of SO ranged from 12% to 62% in men and 2% to 74% in female according to different definitions. SO prevalence was lowest using the Baumgartner criteria (all: 8%, men 12%, women: 2%) and highest according to the Janssen criteria 2 (all: 57%, men 46%, women 74%). There were 45 deaths during a median follow-up period of 44 (20, 76) months. SO by any definition was not statistically significantly associated with mortality during follow-up. Conclusions The current SO definitions are not applicable to predict increased risk of death in MHD patients. We found high degree of variation in the rates of SO when using different definitions. Future studies should focus on establishing MHD population-specific thresholds of muscle mass and adiposity for accurate prognostication.

Background Recent data suggest that sodium (Na+) is stored in the muscle and skin without commensurate water retention in maintenance hemodialysis (MHD) patients. In this study, we hypothesized that excessive Na+ accumulation would be associated with abnormalities in peripheral insulin action. Methods Eleven MHD patients and eight controls underwent hyperinsulinemic–euglycemic–euaminoacidemic clamp studies to measure glucose (GDR) and leucine disposal rates (LDR), as well as lower left leg 23Na magnetic resonance imaging to measure Na+ concentration in the muscle and skin tissue. Results The median GDR and LDR levels were lower, and the median muscle Na+ concentration was higher in MHD patients compared with controls. No significant difference was found regarding skin Na+ concentration between group comparisons. Linear regression revealed inverse relationships between muscle Na+ concentration and GDR and LDR in MHD patients, whereas no relationship was observed in controls. There was no association between skin Na+ content and GDR or LDR in either MHD patients or controls. Conclusions These data suggest that excessive muscle Na+ content might be a determinant of IR in MHD patients, although the causality and mechanisms remain to be proven.

Background. Chronic systemic inflammation is common in patients with chronic kidney disease on dialysis (CKD5D) and has been considered a key mediator of the increased cardiovascular risk in this patient population. In this study, we tested the hypothesis that supplementation of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) will attenuate the systemic inflammatory process in CKD5D patients. Methods. The design was a randomized, double-blinded, placebo controlled pilot trial (NCT00655525). Thirty-eight patients were randomly assigned in a 1:1 fashion to receive 2.9 g of eicosapentaenoic acid (C20:5, n-3) plus docosahexaenoic acid (C22:6, n-3) versus placebo for 12 weeks. The primary outcome was change in pro-inflammatory chemokines measured by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs). Secondary outcomes were changes in systemic inflammatory markers. Analysis of covariance was used to compare percent change from baseline to 12 weeks. Results. Thirty-one patients completed 12 weeks and three patients completed 6 weeks of the study. Median age was 52 (interquartile range 45, 60) years, 74% were African-American and 79% were male. Supplementation of ω-3 PUFAs effectively decreased the LPS-induced PBMC expression of RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) and MCP-1 (Monocyte Chemotactic Protein-1; unadjusted P = 0.04 and 0.06; adjusted for demographics P = 0.02 and 0.05, respectively). There was no significant effect of the intervention on serum inflammatory markers (C-reactive protein, interleukin-6 and procalcitonin). Conclusions. The results of this pilot study suggest that supplementation of ω-3 PUFAs is beneficial in decreasing the levels of endothelial chemokines, RANTES and MCP-1. Studies of larger sample size and longer duration are required to further evaluate effects of ω-3 PUFAs on systemic markers of inflammation, other metabolic parameters and clinical outcomes, particularly cardiovascular outcomes in CKD5D patients.

Chronic inflammation is highly prevalent in maintenance hemodialysis (MHD) patients and associates with increased mortality. IL-1β, a pro-inflammatory cytokine, is elevated in MHD patients. A balance between IL-1β and its naturally occurring antagonist may determine the inflammatory response and its consequences in this population. We performed a pilot randomized placebo-controlled trial to evaluate the efficacy of the administration of recombinant human IL-1 receptor antagonist (IL-1ra) on biomarkers of inflammation and nutrition in MHD patients with three consecutive high sensitivity C-reactive protein (hsCRP) measurements >5 mg/L. We randomly assigned 22 patients to placebo or IL-1ra (1:1) for 4 weeks; 14 completed the trial. Patients in the IL-1ra arm had a 53% reduction in mean hsCRP compared with 1% in the placebo arm (P = 0.008), a 40% reduction in mean IL-6 levels compared with a 20% increase in the placebo arm (P = 0.03), and a 23% increase in mean prealbumin compared with 6% in the placebo arm (P = NS). In conclusion, the administration of IL-1ra in MHD patients can lower biomarkers of inflammation. Whether IL-1ra administration improves survival in this population requires additional long-term studies.