Abdul Rashid Qureshi

BACKGROUND AND OBJECTIVES: Reduced muscle mass and strength are prevalent conditions in dialysis patients. However, muscle strength and muscle mass are not congruent; muscle strength can diminish even though muscle mass is maintained or increased. This study addresses phenotype and mortality associations of these muscle dysfunction entities alone or in combination (i.e., concurrent loss of muscle mass and strength/mobility, here defined as sarcopenia). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study included 330 incident dialysis patients (203 men, mean age 53±13 years, and mean GFR 7±2 ml/min per 1.73 m(2)) recruited between 1994 and 2010 and followed prospectively for up to 5 years. Low muscle mass (by dual-energy x-ray absorptiometry appendicular mass index) and low muscle strength (by handgrip) were defined against young reference populations according to the European Working Group on Sarcopenia in Older People. RESULTS: Whereas 20% of patients had sarcopenia, low muscle mass and low muscle strength alone were observed in a further 24% and 15% of patients, respectively. Old age, comorbidities, protein-energy wasting, physical inactivity, low albumin, and inflammation associated with low muscle strength, but not with low muscle mass (multivariate ANOVA interactions). During follow-up, 95 patients (29%) died and both conditions associated with mortality as separate entities. When combined, individuals with low muscle mass alone were not at increased risk of mortality (adjusted hazard ratio [HR], 1.23; 95% confidence interval [95% CI], 0.56 to 2.67). Individuals with low muscle strength were at increased risk, irrespective of their muscle stores being appropriate (HR, 1.98; 95% CI, 1.01 to 3.87) or low (HR, 1.93; 95% CI, 1.01 to 3.71). CONCLUSIONS: Low muscle strength was more strongly associated with aging, protein-energy wasting, physical inactivity, inflammation, and mortality than low muscle mass. Assessment of muscle functionality may provide additional diagnostic and prognostic information to muscle-mass evaluation.

Various studies suggest a strong association between nutrition and clinical outcome in hemodialysis (HD) patients. Several morbidity factors that per se increase the risk of a poor outcome, such as cardiovascular disease (CVD) and inflammation, may also cause malnutrition. Among laboratory parameters used to assess nutritional status, serum albumin appears to be a particularly strong predictor of morbidity and mortality. This study assessed the importance of nutritional status and inflammation and other comorbidity factors as predictors of mortality in HD patients. Nutritional status was evaluated in 128 HD patients by subjective global nutritional assessment (SGNA) and by measuring several anthropometric markers (actual body weight, percentage of actual body weight to desirable body weight, midarm muscle circumferences, triceps skinfold thickness), and serum albumin, plasma insulin such as insulin growth factor-1 and as a marker of inflammation, serum C-reactive protein (s-CRP) levels. The mortality during the next 36 mo was analyzed in relation to age, gender, CVD, SGNA, serum albumin, CRP, and several other factors by Kaplan-Meier analysis multivariate. Cox proportional hazard analysis was used to identify independent predictors of mortality. After 36 mo, 58 patients were still on HD treatment, 57 patients (45%) had died while receiving treatment, and 13 had received a kidney transplant. The main cause of death was CVD (58%), followed by infection (18%); malnutrition/cachexia was a rare direct cause of death (5%). Kaplan-Meier analysis showed that age, female gender, CVD, diabetes, SGNA, all anthropometric parameters, serum albumin, plasma insulinlike growth factor-1, and s-CRP were significant predictors of mortality. Analysis by the Cox model showed that age, gender, CVD, nutritional status (SGNA), and CRP were independent predictors of mortality at 36 mo. A low albumin level was not an independent predictor, although it was strongly associated with a reduced survival rate in the Kaplan-Meier analysis. Inflammation, malnutrition, and CVD appeared to contribute to increased mortality in a stepwise manner. The mortality at 36 mo was 0% when none of these complications was present, whereas the mortality was 75% in those patients with all three risk factors present at baseline. It is concluded that in addition to malnutrition and comorbidities (CVD, diabetes mellitus), inflammation (elevated s-CRP) is a significant independent risk factor for mortality in HD patients. Inflammation, malnutrition, and CVD appear to be interrelated, each additionally contributing to the high mortality in these patients.

OBJECTIVE: The lifespan of dialysis patients is as short as in patients with metastatic cancer disease, mainly due to cardiovascular disease (CVD). DNA methylation is an important cellular mechanism modulating gene expression associated with ageing, inflammation and atherosclerotic processes. DESIGN: DNA methylation was analysed in peripheral blood leucocytes from three different groups of chronic kidney disease (CKD) populations (37 CKD stages 3 and 4 patients, 98 CKD stage 5 patients and 20 prevalent haemodialysis patients). Thirty-six healthy subjects served as controls. Clinical characteristics (diabetes mellitus, nutritional status and presence of clinical CVD), inflammation and oxidative stress biomarkers, homocysteine and global DNA methylation in peripheral blood leucocytes (defined as HpaII/MspI ratio by the Luminometric Methylation Assay method) were evaluated. CKD stage 5 patients (n=98) starting dialysis treatment were followed for a period of 36 +/- 2 months. RESULTS: Inflamed patients had lower ratios of HpaII/MspI, indicating global DNA hypermethylation. Analysis by the Cox regression model demonstrated that DNA hypermethylation (HpaII/MspI ratio <median) was significantly associated with both all-cause (RR 5.0; 95% CI: 1.7-14.8; P<0.01) and cardiovascular (RR 13.9; 95% CI: 1.8-109.3; P<0.05) mortality, even following the adjustment for age, CVD, diabetes mellitus and inflammation. CONCLUSION: The present study demonstrates that global DNA hypermethylation is associated with inflammation and increased mortality in CKD.