Background
Excess extracellular volume is a major clinical problem in patients with chronic kidney disease (CKD) and causes lower extremity edema, hypertension, pulmonary vascular congestion or edema, and heart failure [
1]. However, whether excess extracellular volume is associated with kidney disease progression is unclear, and such studies are hampered by the lack of suitable markers of hypervolemia. In bioimpedance analysis (BIA), the ratio of extracellular water (ECW) to total body water (TBW) has been used as an indicator of the fluid volume status [
2‐
6]. However, the ECW/TBW ratio may not be an ideal measurement of volume overload. The ECW/TBW ratio is affected not only by changes in the ECW, but also by changes in the intracellular water (ICW) component of TBW. The amount of ICW decreases with aging [
7]. Therefore, an increased ECW/TBW ratio may be also observed in lean, elderly patients without edema. Using the Body Composition Monitor, which assesses the extracellular volume status by comparing the measured ECW to the expected ECW, Tsai et al. recently reported an association between fluid overload and adverse kidney outcomes in the short term in patients with advanced stage 4 to 5 CKD [
8].
Anthropometric formulas combined with tracer dilution techniques have been extensively used to calculate TBW in patients with CKD. The Watson formula, which is routinely used to calculate the efficiency of dialysis, was originally derived from pooled data of healthy subjects and provides information about adequate fluid volume adjusted for age and sex [
9]. We hypothesized that the ratio of the ECW as measured by BIA (ECW
BIA) to the TBW as calculated using the Watson formula (TBW
Watson) might also be used to assess the extracellular fluid status in clinical practice. In addition, we assessed the extracellular volume status using the ratio of the measured ECW to the expected ECW as calculated by an equation described by Peters et al. based on healthy potential renal transplant donors [
10].
The goals of the present study were to (1) identify factors associated with the extracellular volume status, (2) investigate the relationship between the extracellular volume status and renal outcomes in patients with CKD and n study the prognostic performance of parameters associated with the extracellular volume status in predicting adverse renal outcomes.
Discussion
This study revealed that the ECWBIA/TBWWatson ratio reflects the extracellular volume status and is associated with adverse renal outcomes in patients with CKD. Additionally, our findings showed that the %ECWBIA/TBWWatson ratio is influenced by sex and proteinuria. Finally, age affected the balance between the ICW and ECW and increased the percentage of ECW in the body fluid composition.
BIA methods are used to noninvasively measure the ECW, ICW, and TBW and calculate the free fat mass and fat based on empirical equations [
19]. However, the measure of free fat mass is influenced by the TBW content because the fat free mass is obtained by dividing the TBW by 0.733. The ECW
BIA/TBW
BIA ratio increases along with ECW excess and decreased ICW. Therefore, the ECW
BIA/TBW
BIA ratio appears to be an inadequate marker of the volume status [
7]. In fact, the present findings show that the percentage of ECW
BIA in TBW
BIA was positively correlated with age. Two recent studies used a new BIA device to assess the volume status [
8,
20]. The device quantified fluid overload using reference values derived from the pooled data of healthy subjects [
21]. We preliminarily used the expected ECW as calculated by the Peters formula and the expected TBW as calculated by the Watson formula as reference values of body fluid composition. These two parameters were highly correlated with each other in our study population (
r = 0.97 for men and
r = 0.98 for women) (data not shown). Peters et al. reported that the ECW was retained in healthy potential donors of older ages [
10]. On the other hand, the Watson formula includes age in men as a coefficient. The measured ECW
BIA gradually decreased with age in our study. As a result, elderly patients tended to exhibit a lower ECW
BIA/ECW
Peters ratio. The ECW
BIA/ECW
Peters ratio may be not a useful maker if the extracellular volume changes with age only in patients with CKD and not in healthy subjects. The present findings show that the ratio of the measured extracellular volume to the estimated body fluid volume can serve as a useful marker of the volume status in patients with CKD. This result may be one reason that the %ECW
BIA/TBW
Watson ratio exhibited a relative increase in the extracellular volume with respect to the expected fluid status, resulting in a good balance between the ICW and ECW for age. Notably, a higher extracellular volume was associated with adverse renal outcomes during a relatively long follow-up period (median duration of 4.9 years) for both of the ECW
BIA/ECW
Peters ratio and the %ECW
BIA/TBW
Watson ratio. Additionally, the ECW
BIA/TBW
Watson ratio was associated with traditional risk factors for kidney disease progression, including age, male sex, diabetes mellitus, higher pulse pressure, resistant hypertension, lower eGFR, lower serum albumin level, and higher proteinuria level. These findings may suggest that a higher extracellular volume causes hemodynamic instability. In contrast, sodium excretion was not associated with fluid excess. Whether sodium intake and sodium retention have a one-to-one relationship and whether sodium intake is linearly associated with the development of end-stage renal disease remain unclear [
22‐
24]. Younger subjects and those without uremia consume a higher variety of foods with various levels of sodium, protein, and total calories than do elderly people and patients with uremia. These biases may have hampered studies in this area.
Proteinuria was a strong factor in the development of a higher extracellular volume. Hypoalbuminemia, mostly in association with massive proteinuria, produces an increased interstitial fluid volume and a contracted intravascular volume contraction by a diminished oncotic pressure gradient, thus inducing renal sodium retention by activation of the renin-angiotensin-aldosterone system [
25]. In addition, differences in all parameters of the extracellular volume status were found between men and women; specifically, it the extracellular volume was lower in women. The ECW and ICW contents are generally lower in women than in men because women have a relatively higher proportion of fat. Otherwise, differences between these two parameters may be caused by inaccuracies in the determination of the measured fluid content and estimated fluid content. Our findings revealed a difference between the measured TBW
BIA and estimated TBW
Watson in both men and women (Additional file
2: Figure S1). In both sexes, these differences increased with increases in the measured TBW
BIA (Additional file
2: Figure S1B and D). Thus, differences between the actual values and reference values may contribute to the fluid volume status. The Watson formula was designed to estimate the TBW of healthy Caucasian subjects; however, it must be interpreted with caution because it may overestimate the TBW
Watson in Japanese patients, especially women. A previous study reported differences in the TBW among individuals of different races [
26].
Aging cells are known to shrink and undergo apoptosis [
27‐
29]. Fluid imbalance in patients with CKD is characterized by excess ECW associated with sodium retention [
30,
31] and decreased ICW associated with malnutrition [
32]. In fact, patients with CKD with a leaner body mass have a higher prevalence of hypertension, poorer control of hypertension, and greater incidence of left ventricular hypertrophy. This phenomenon is known as the "obesity paradox" [
33,
34]. Our findings highlight the notion that elderly patients with CKD may be more susceptible to volume overload because the reduced intracellular volume caused by aging and malnutrition lessens the capacity of cells to retain fluid. This strongly supports the hypothesis that a lower serum albumin level is significantly correlated with the fluid volume.
The best %ECWBIA/TBWWatson ratio cut-offs for adverse renal outcomes among male, female, and all patients were 42.2%, 40.0%, and 39.9%, respectively. These values were close to the ECW/ICW ratio of 2:3. The abovementioned threshold values may be useful for determining extracellular volume excess. However, whether removal of excess fluid improves renal outcomes remains unclear.
This study has several limitations. First, it was a retrospective cohort study conducted at a single center. However, it provided detailed information on patients’ body fluid composition and had a relatively long follow-up period. Second, the ECW
BIA/TBW
Watson ratio may not be a precise indicator of volume status; the estimated TBW
Watson and actual TBW
BIA differ in Japanese patients. We recognize that this parameter was not compared with an indicator for congestive heart failure, such as the N-terminal of the prohormone brain natriuretic peptide. Regardless, the ECW
BIA/TBW
Watson ratio is associated with many factors associated with fluid volume overload; BIA can be used to easily and noninvasively assess the body fluid composition, and the results correlate with those of isotopic dilution and dual-energy X-ray absorptiometry [
35]. The estimated TBW
Watson is widely used in this area. We believe that the ECW
BIA/TBW
Watson ratio is a practical parameter of the extracellular volume status and that the reported data will support future studies in this area.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
RT, YO, and SM conceived of the study. SM and YO contributed to the sample acquisition. RT and YO analyzed and interpreted the data. AA and KS provided scientific advice in their field of expertise. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.