Estimation of homeostatic dysregulation and frailty using biomarker variability: a principal component analysis of hemodialysis patients.

Increased intraindividual variability in several biological parameters is associated with aspects of frailty and may reflect impaired physiological regulation. As frailty involves a cumulative decline in multiple physiological systems, we aimed to estimate the overall regulatory capacity by applying a principal component analysis to such variability. The variability of 20 blood-based parameters was evaluated as the log-transformed coefficient of variation (LCV) for one year's worth of data from 580 hemodialysis patients. All the LCVs were positively correlated with each other and shared common characteristics. In a principal component analysis of 19 LCVs, the first principal component (PC1) explained 27.7% of the total variance, and the PC1 score exhibited consistent correlations with diverse negative health indicators, including diabetes, hypoalbuminemia, hyponatremia, and relative hypocreatininemia. The relationship between the PC1 score and frailty was subsequently examined in a subset of the subjects. The PC1 score was associated with the prevalence of frailty and was an independent predictor for frailty (odds ratio per SD: 2.31, P = 0.01) using a multivariate logistic regression model, which showed good discrimination (c-statistic: 0.85). Therefore, the PC1 score represents principal information shared by biomarker variabilities and is a reasonable measure of homeostatic dysregulation and frailty.

Aging and death-associated changes in serum albumin variability over the course of chronic hemodialysis treatment.

BACKGROUND: Several epidemiological studies have demonstrated associations between variability in a number of biological parameters and adverse outcomes. As the variability may reflect impaired homeostatic regulation, we assessed albumin variability over time in chronic hemodialysis (HD) patients. METHODS: Data from 1346 subjects who received chronic HD treatment from May 2001 to February 2015 were analyzed according to three phases of HD treatment: post-HD initiation, during maintenance HD treatment, and before death. The serum albumin values were grouped according to the time interval from HD initiation or death, and the yearly trends for both the albumin levels and the intra-individual albumin variability (quantified by the residual coefficient of variation: Alb-rCV) were examined. The HD initiation and death-associated changes were also analyzed using generalized additive mixed models. Furthermore, the long-term trend throughout the maintenance treatment period was evaluated separately using linear regression models. RESULTS: Albumin levels and variability showed distinctive changes during each of the 3 periods. After HD initiation, albumin variability decreased and reached a nadir within a year. During the subsequent maintenance treatment period (interquartile range = 5.2-11.0 years), the log Alb-rCV showed a significant upward trend (mean slope: 0.011 ± 0.035 /year), and its overall mean was -1.49 ± 0.08 (equivalent to an Alb-rCV of 3.22%). During the 1-2 years before death, this upward trend clearly accelerated, and the mean log Alb-rCV in the last year of life was -1.36 ± 0.17. The albumin levels and variability were negatively correlated with each other and exhibited exactly opposite movements throughout the course of chronic HD treatment. Different from the albumin levels, albumin variability was not dependent on chronological age but was independently associated with an individual's aging and death process. CONCLUSION: The observed upward trend in albumin variability seems to be consistent with a presumed aging-related decline in homeostatic capacity.

Variability of laboratory parameters is associated with frailty markers and predicts non-cardiac mortality in hemodialysis patients.

BACKGROUND: The levels of many laboratory parameters are associated with the outcomes of dialysis patients, but the significance of their variability has not been well studied. METHODS: A total of 384 patients receiving stable hemodialysis treatment during 2002 were followed up for mortality until the end of 2013. The within-patient coefficients of variation (CV) were calculated for 13 laboratory parameters from 1 year of data. We defined variability as CV and analyzed the survival of the patients according to the baseline CV values of each parameter by proportional hazard modeling. RESULTS: During the 11-year observation period, 125 patients died. Higher CV levels for eight parameters, namely, blood urea nitrogen (BUN), sodium, hemoglobin, creatinine, total protein, albumin, potassium and phosphate, were significantly associated with all-cause mortality. The adjusted hazard ratios for a high BUN-CV (>15 %) and a high Na-CV (>1.3 %) against a lower CV were 1.92 (95 % CI 1.31-2.81) and 1.95 (1.36-2.80), respectively. The increased mortality risk associated with each variability was attributed to excess non-cardiac deaths. The CV values of most parameters were correlated with each other and often exhibited negative associations with age, diabetes, and mobility as well as the levels of hemoglobin, albumin, creatinine, Na, the protein catabolic rate, and the creatinine generation rate. Therefore, a high variability was generally associated with frailty-related adverse prognostic factors. CONCLUSIONS: The variability of several blood parameters had a significant impact on all-cause and non-cardiac mortality. The levels of the variabilities were most likely related to poor physical conditions of the patients.