Research Article: Extracellular Fluid/Intracellular Fluid Volume Ratio as a Novel Risk Indicator for All-Cause Mortality and Cardiovascular Disease in Hemodialysis Patients

Date Published: January 18, 2017

Publisher: Public Library of Science

Author(s): Eun-Jung Kim, Myung-Jin Choi, Jeoung-Hwan Lee, Ji-Eun Oh, Jang-Won Seo, Young-Ki Lee, Jong-Woo Yoon, Hyung-Jik Kim, Jung-Woo Noh, Ja-Ryong Koo, Tatsuo Shimosawa.


In hemodialysis patients, fluid overload and malnutrition are accompanied by extracellular fluid (ECF) expansion and intracellular fluid (ICF) depletion, respectively. We investigated the relationship between ECF/ICF ratio (as an integrated marker reflecting both fluid overload and malnutrition) and survival and cardiovascular disease (CVD) in the context of malnutrition-inflammation-arteriosclerosis (MIA) complex.

Seventy-seven patients from a single hemodialysis unit were prospectively enrolled. The ECF/ICF volume was measured by segmental multi-frequency bioimpedance analysis. MIA and volume status were measured by serum albumin, C-reactive protein (CRP), pulse wave velocity (PWV) and plasma B-type natriuretic peptide (BNP), respectively.

The mean ECF/ICF ratio was 0.56±0.06 and the cut-off value for maximum discrimination of survival was 0.57. Compared with the low ECF/ICF group, the high ECF/ICF group (ratio≥0.57, 42%) had higher all-cause mortality, CVD, CRP, PWV, and BNP, but lower serum albumin. During the 5-year follow-up, 24 all-cause mortality and 38 CVD occurred (18 and 24, respectively, in the high ECF/ICF group versus 6 and 14 respectively in the low ECF/ICF group, P<0.001). In the adjusted Cox analysis, the ECF/ICF ratio nullifies the effects of the MIA and volume status on survival and CVD and was an independent predictor of all-cause mortality and CVD: hazard ratio (95% confidence interval); 1.12 (1.01–1.25) and 1.09 (1.01–1.18) for a 0.01 increase in the ECF/ICF ratio. The degree of malnutrition (albumin), inflammation (CRP), arteriosclerosis (PWV), and fluid overload (BNP) were correlated well with the ECF/ICF ratio. Hemodialysis patients with high ECF/ICF ratio are not only fluid overloaded, but malnourished and have stiff artery with more inflammation. The ECF/ICF ratio is highly related to the MIA complex, and is a major risk indicator for all-cause mortality and CVD.

Partial Text

For a long time, fluid overload and malnutrition have been known to be major risk factors for morbidity and mortality in chronic hemodialysis patients [1–3]. Recently, a strong association between malnutrition, inflammation, and arteriosclerosis/atherosclerosis (the so-called MIA syndrome) have been described and proposed as the main causes of morbidity and mortality in chronic hemodialysis patients [1, 4–6]. Among the MIA components, inflammation seems to play a pivotal role in the pathogenesis of malnutrition and arteriosclerosis by the following mechanisms: (1) inflammatory response is responsible for malnutrition by increased protein catabolism and muscle wasting [4, 6]; and (2) uremic inflammation is known to promote extra-osseous deposition of calcium to vessel walls, resulting in vascular calcification and arteriosclerosis [7].

The characteristics of the cohort at the time of inclusion are shown in Table 1. The mean ECF/ICF ratio was 0.56±0.06. During the 5-year follow-up, 24 all-cause mortality and 38 new cardiovascular events occurred. The cut-off ECF/ICF ratio for maximum discrimination of all-cause mortality by survival analysis was 0.57. The comparisons according to the cut-off ECF/ICF ratio are shown in Table 2. Compared with the low ECF/ICF group (ECF/ICF ratio<0.57), the high ECF/ICF group (ECF/ICF ratio≥0.57) had higher all-cause mortality, CVD, systolic blood pressure (BP), pulse pressure, number of antihypertensive pills, and LVMI, but lower hemodialysis duration, hemoglobin, BUN, serum creatinine, plasma intact PTH, and serum phosphate. The mean age and proportions of patients with diabetes and prior CVD were also higher in the high ECF/ICF ratio group. This was the first study to show that the ECF/ICF ratio, as measured by MF-BIA, can be used as a novel risk indicator for all-cause mortality and CVD in chronic hemodialysis patients. In this population of patients, higher ECF volume represents fluid excess, while lower ICF volume represents malnutrition (or low body cell mass) [12,13]. Both chronic fluid overload and malnutrition are well-recognized factors contributing to the high morbidity and mortality in hemodialysis patients. However, there are many confounding interactions between fluid volume and nutritional status in chronic hemodialysis patients, especially in the context of the MIA complex. For example, fluid overload and bowel edema could lead to altered gut permeability to bacteria and/or endotoxins, and the subsequent translocation of these materials into the circulation. Translocated bacteria and/or endotoxins within the circulation could be an important stimulus of systemic immune activation and cytokine production [9]. In chronic hemodialysis patients, fluid overload-induced arterial distension is also associated with increased aortic PWV (Laplace’s law); better management of fluid overload leads to a significant decrease in arterial PWV and stiffness [10, 20]. Conversely, inflammation-induced hypoalbuminemia and increased vascular permeability enhance extravascular fluid shift, thereby resulting in ECF volume overload [11]. It is also well known that inflammatory conditions can cause loss of muscle mass through the activation of the ubiquitin-proteasome proteolytic system [21]. This depletion in body cell mass could eventually lead to a decrease in the ICF volume and a relative increase in the ECF/ICF volume ratio.   Source: