Visual Abstract
Keywords: cell volume, dialysis, geriatric nephrology, hemodialysis, malnutrition, protein-energy wasting, quality of life, water-electrolyte balance
Abstract
Key Points
Both low skeletal muscle mass index and high extracellular and intracellular water independently predicted mortality; risk was highest when both abnormalities were present.
Extracellular and intracellular water ≥0.66 indicated impaired muscle tissue integrity and helped identify vulnerable patients.
Combining skeletal muscle mass index with extracellular and intracellular water identified patients with lower health-related quality of life across multiple domains.
Background
Decreased skeletal muscle mass is common in hemodialysis patients and contributes to adverse outcomes. However, muscle mass alone does not fully capture muscle health. An imbalance between extracellular and intracellular water (ECW/ICW ratio) may reflect tissue-level integrity of skeletal muscle. This study examined the combined prognostic significance of the skeletal muscle mass index (SMI) and ECW/ICW ratio for mortality and health-related quality of life (HRQoL) in hemodialysis patients.
Methods
In this multicenter cohort study, 295 maintenance hemodialysis patients (208 men, 87 women) underwent multifrequency bioelectrical impedance analysis. Low SMI was defined according to the Asian Working Group for Sarcopenia (men <7.0 kg/m2, women <5.7 kg/m2), and high ECW/ICW was defined as ≥0.66. Patients were categorized into four groups based on SMI and ECW/ICW status. HRQoL was assessed using the Kidney Disease Quality of Life Short Form, and mortality was recorded through March 2024.
Results
Among the cohort, 93 patients (31.5%) had low SMI and 38 (12.9%) had both low SMI and high ECW/ICW. These patients were older and demonstrated lower intracellular water, poorer nutritional status, chronic inflammation, and higher natriuretic peptide levels. During a median follow-up of 3.7 years, 34 patients died. Low SMI (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.11 to 3.65) and high ECW/ICW (HR, 2.21; 95% CI, 1.34 to 4.08) independently predicted mortality, while their coexistence conferred the highest risk (HR, 3.95; 95% CI 2.01 to 7.72). Both indices were associated with impaired HRQoL across multiple domains, particularly those related to physical functioning.
Conclusions
Combined assessment of SMI and ECW/ICW identifies muscle vulnerability and predicts mortality and HRQoL in hemodialysis patients. This simple, noninvasive approach may improve early detection of high-risk individuals and inform targeted interventions addressing nutrition, inflammation, and fluid management.
Introduction
Aging of the population undergoing maintenance hemodialysis has progressed rapidly in recent years, revealing a high prevalence of frailty among these patients.1,2 Frailty in dialysis patients is a multifactorial syndrome associated with adverse clinical outcomes, including reduced health-related quality of life (HRQoL), increased risk of falls and fractures, hospitalization, and mortality.3–5 One of the major contributors to frailty is sarcopenia, a condition characterized by progressive loss of skeletal muscle mass and strength.6
The Asian Working Group for Sarcopenia defines sarcopenia using a comprehensive assessment of muscle strength (e.g., handgrip strength), physical performance (e.g., gait speed), and skeletal muscle mass index (SMI).7 This framework enables the evaluation of both skeletal muscle quantity and its functional aspects in clinical practice. Although reduced muscle mass remains a key diagnostic component, increasing attention has shifted toward functional measures—such as strength and physical performance—particularly in chronic conditions like ESKD.8 However, assessing grip strength and gait speed is time-consuming and requires patient cooperation.
Bioelectrical impedance analysis (BIA) is a noninvasive and practical tool that simultaneously evaluates skeletal muscle mass and body fluid distribution. In dialysis practice, fluid assessment has traditionally focused on extracellular water (ECW) expansion resulting from sodium retention. By contrast, accumulating evidence indicates that decreased intracellular water (ICW)—a feature associated with aging, sarcopenia, and cellular apoptosis—may be more strongly linked to adverse outcomes.9,10 Moreover, the malnutrition-inflammation-fluid overload (MIFO) syndrome highlights the complex interactions among these pathophysiologic processes.11 The ECW/ICW ratio, which is linearly related to the ECW-to-total body water ratio (ECW/TBW), reflects not only extracellular fluid expansion but also reduced cellular density within tissues, particularly skeletal muscle.8,12,13 Thus, it serves as an integrated indicator of muscle tissue integrity.
Accordingly, we hypothesized that combining SMI with the ECW/ICW ratio may offer a more comprehensive characterization of skeletal muscle—capturing not only its quantity but also its tissue-level integrity—thereby improving prognostic evaluation for mortality and HRQoL in patients undergoing maintenance hemodialysis.
Methods
Study Design and Participants
This multicenter cohort study, including both cross-sectional and prospective components, was conducted between 2019 and 2022 at four maintenance hemodialysis centers: Seijinkai Mihama Hospital, Seijinkai Mihama Sakura Clinic, Seijinkai Narita Clinic, and Seijinkai Katori Clinic.
Eligible participants were adults 20 years or older who had been undergoing maintenance hemodialysis for at least 90 days and had a stable dialysis prescription for at least 30 days before enrollment. Of the 319 patients who provided written informed consent to participate in the HRQoL survey, 295 with complete data were included in the analysis. Exclusion criteria were as follows: coronary and/or valvular interventions or myocardial infarction within the past 6 months; hospitalization for heart failure requiring unplanned dialysis within the past 6 months; contraindications to BIA (e.g., pacemaker, joint replacement, or mechanical heart valve); pregnancy; major limb amputation; advanced malignancy; or diagnosis of dementia.
Data Collection
The baseline data included patient age, sex, anthropometric measurements, diabetes mellitus status, hemodialysis vintage, height, body weight, and predialysis and postdialysis BP. Standard laboratory parameters were measured during the long interdialytic interval session (the first dialysis session of the week), at the beginning of each month. These included serum albumin, BUN, creatinine, sodium, potassium, chloride, calcium, phosphorus, total cholesterol, triglycerides, glucose, uric acid, hemoglobin (Hb), C-reactive protein, intact parathyroid hormone, and β2-microglobulin. Dialysis adequacy was assessed using the Shinzato formula based on the urea reduction ratio and single-pool Kt/Vurea.14 The Geriatric Nutritional Risk Index (GNRI) was calculated using the following formula: GNRI=14.89+serum albumin (g/dl)+(41.7×body weight/ideal body weight). Ideal body weight was determined based on patient height, assuming an ideal body mass index of 22 kg/m2.15 Postdialysis human atrial natriuretic peptide (hANP) levels were determined using a chemiluminescent enzyme immunoassay system (CL-JACK RK; Minaris Medical Co., Ltd., Tokyo, Japan). Postdialysis chest radiographs were obtained to calculate the cardiothoracic ratio, defined as the ratio of the maximum transverse cardiac diameter to the maximum thoracic diameter, which serves as an indicator of volume overload.
Assessment of Body Fluid Composition
Standard multifrequency bioelectrical impedance analysis (MF-BIA) was performed with the patient in the supine position on a flat, nonconductive bed immediately after hemodialysis. For the body composition assessment, a segmental MF-BIA device (InBody S10, InBody Co., Ltd., Seoul, Korea; https://inbodyusa.com/) equipped with eight tactile electrodes was used. Microprocessor-controlled switches and an impedance analyzer were activated, and the segmental resistance values of the arms, trunk, and legs were measured at four frequencies (5, 50, 250, and 500 kHz). Twenty segmental resistance measurements were obtained for each participant. These measurements were then processed using MF-BIA software (InBody S10; InBody Co., Ltd., Seoul, Korea; https://inbodyusa.com/) to calculate total body water, ICW, ECW, and the ECW/ICW ratio. SMI was calculated as the appendicular skeletal muscle mass divided by height squared (kg/m2), where appendicular skeletal muscle mass was defined as the sum of lean soft tissue in both the upper and lower limbs.
Low SMI was defined according to the Asian Working Group for Sarcopenia 2019 criteria (<7.0 kg/m2 for men, <5.7 kg/m2 for women).7 These sex-specific values are derived from reference populations of healthy Asian adults and have been widely adopted in clinical research to identify individuals at risk for sarcopenia.
In this study, we selected 0.66 as the cutoff value for the ECW/ICW ratio. This decision was based on previous studies showing that elevated ECW/ICW values—typically ranging from 0.57 to 0.66—correlate with fluid imbalance and adverse clinical outcomes in hemodialysis patients.13,16 In addition, the commonly accepted physiologic range of ECW/TBW (0.36–0.40) corresponds mathematically to an ECW/ICW ratio of approximately 0.56–0.67,17,18 supporting the interpretation that values near 0.66 represent a marked deviation from normal body fluid distribution.
HRQoL assessment
HRQoL was assessed using the Kidney Disease Quality of Life Short Form version 1.3, a validated modification of the 36-Item Short Form Health Survey (SF-36), developed specifically for dialysis patients.19 Eight generic domains were evaluated: physical functioning, role limitations due to physical health, bodily pain, general health, vitality, social functioning, role limitations due to emotional health, and emotional well-being.
Statistical Analyses
Statistical analyses were performed using JMP Pro (version 17.0; SAS Institute Inc., Cary, NC). Continuous variables were compared across the four SMI/ECW-ICW subgroups using the Kruskal–Wallis test, followed by Steel-Dwass multiple comparison tests when appropriate. Categorical variables were analyzed using the Fisher exact test or Pearson chi squared test.
Survival analyses were conducted using Cox proportional hazards models. Univariate and multivariable models were used to assess the independent associations of low SMI and high ECW/ICW with mortality. To evaluate their combined influence, we additionally fitted models including both main effects and an interaction term, as well as pairwise Cox models comparing the four SMI/ECW-ICW subgroups. Raw P values from these subgroup comparisons were adjusted using the Holm method.
Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff values for SMI and ECW/ICW. A two-tailed P value < 0.05 was considered statistically significant.
Ethics Statement
This study was approved by the Ethics Committee of Toho University Sakura Medical Center, Tokyo, Japan (Approval No. S24012_S21073 [S18086]), and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all the participants.
Results
Population Characteristics
The baseline characteristics of the study population (208 men and 87 women) are summarized in Table 1. Patients were categorized into four groups based on SMI and the ECW/ICW ratio: normal SMI with normal ECW/ICW (<0.66), normal SMI with high ECW/ICW (≥0.66), low SMI with normal ECW/ICW, and low SMI with high ECW/ICW. Overall, 93 patients (31.5%) had a low SMI, and 38 (12.9%) had a high ECW/ICW ratio. Patients in the low SMI/high ECW/ICW group were generally older and showed biochemical profiles consistent with nutritional wasting, chronic inflammation, and fluid overload, as reflected by lower serum albumin or GNRI values and higher C-reactive protein and hANP levels.
Table 1.
Population characteristics according to normal skeletal muscle mass index group with or without extracellular and intracellular water ratio <0.66 and low skeletal muscle mass index group with or without extracellular and intracellular water ratio <0.66
| Patients Characteristics | Normal SMI Group, kg/m2 Men ≥7.0 or Women ≥5.7 (n=202, 68.5%) |
Low SMI Group, kg/m2 Men <7.0 or Women <5.7 (n=93, 31.5%) |
P for Overall Comparison | ||
|---|---|---|---|---|---|
| ECW/ICW <0.66 (n=148, 50.2%) | ECW/ICW ≥0.66 (n=54, 18.3%) | ECW/ICW <0.66 (n=55, 18.6%) | ECW/ICW ≥0.66 (n=38, 12.9%) | ||
| Age, yr | 61 (51–61) | 72 (64–77)a | 71 (59–76)a | 74 (68–80)a | <0.001 |
| Men, n (%) | 115(78) | 36(67)a | 35(64)a | 22(58)a | 0.04 |
| Diabetes mellitus, n (%) | 69(47) | 23(43) | 23(42) | 16(42) | 0.60 |
| Dialysis vintage, mo | 65(30–117) | 78(40–151) | 71(40–129) | 98(59–265)a,b | 0.024 |
| Cardiovascular disease, n (%) | 25(17) | 14(26) | 8(15) | 10(26) | 0.27 |
| BMI, kg/m2 | 23.7(21.2–26.3) | 22.1(19.7–25.3)a | 19.9(18.3–21.4)a,c | 18.9(17.0–20.9)a,c | <0.001 |
| Ultrafiltration volume. L | 3.4(2.7–4.4) | 2.8(2.2–3.3)a | 2.5(2.1–2.8)a | 2.4(2.0–2.9)a | <0.001 |
| Ultrafiltration volume, % of body weight | 5.4(4.3–6.1) | 4.8(3.7–5.5)a | 5.1(4.2–6.2) | 4.9(4.1–6.3) | 0.12 |
| Predialysis systolic BP, mm Hg | 148(132–162) | 150(127–160) | 136(121–156) | 138(121–159) | 0.061 |
| Postdialysis systolic BP, mm Hg | 134(120–148) | 149(130–164)a | 143(119–164) | 145(128–157)a | 0.013 |
| Predialysis diastolic BP, mm Hg | 80(71–90) | 73(66–82)a | 70(61–81)a | 69(60–79)a | <0.001 |
| Postdialysis diastolic BP, mm Hg | 75(69–84) | 76(65–89) | 74(64–83) | 68(63–85) | 0.35 |
| Pulse rate, /min | 72(64–79) | 66(60–74)a | 67(60–74)a | 72(59–80) | 0.005 |
| Serum albumin, mg/dl | 3.6(3.5–3.8) | 3.6(3.4–3.8) | 3.5(3.4–3.7)a | 3.4(3.3–3.6)a,c | <0.001 |
| Blood urea nitrogen, mg/dl | 61.0(51.3–70.8) | 55.0(45.1–62.1)a | 57.6(48.0–72.9)c | 52.7(45.1–59.5)a,b | <0.001 |
| Serum creatinine, mg/dl | 11.4(9.9–12.8) | 9.2(8.1–10.4)a | 9.9(8.9–11.1)a,c | 8.4(7.3–9.1)a,b,c | <0.001 |
| Serum sodium, mEq/L | 139(137–140) | 139(138–140) | 139(137–142) | 139(138–141) | 0.76 |
| Serum potassium, mEq/L | 4.9(4.4–5.4) | 4.7(4.3–5.3) | 4.8(4.3–5.1) | 4.6(4.2–5.0)a | 0.048 |
| Serum chloride, mEq/L | 103(101–105) | 104(102–106) | 104(104–106) | 105(103–106)a | 0.024 |
| Serum calcium, mg/dl | 8.7(8.3–9.0) | 8.6(8.1–9.0) | 8.5(8.2–8.8) | 8.5(8.1–9.1) | 0.11 |
| Serum phosphorus, mg/dl | 5.7(5.0–6.5) | 5.5(4.9–6.2) | 5.4(4.9–6.2) | 5.3(4.7–5.8)a | 0.11 |
| TC, mg/dl | 166(143–188) | 156(136–178) | 173(144–202)c | 156(138–184) | 0.14 |
| TG, mg/dl | 123(83–186) | 84(64–116)a | 80(60–129)a | 81(60–110)a | <0.001 |
| Blood glucose, mg/dl | 112(92–159) | 106(94–129) | 114(94–157) | 108(95–145) | 0.58 |
| Uric acid, mg/dl | 8.0(7.2–9.0) | 7.1(6.4–7.9)a | 7.6(6.9–8.4)a | 6.9(6.6–7.8)a | <0.001 |
| Hemoglobin, g/dl | 11.4(10.8–12.1) | 11.0(10.6–11.8) | 11.2(10.8–11.9) | 11.1(10.2–11.6)a | 0.024 |
| CRP, mg/dl | 0.12(0.05–0.27) | 0.11(0.04–0.19) | 0.08(0.04–0.27) | 0.23(0.08–0.57)a,b,c | 0.038 |
| iPTH, pg/ml | 167(114–234) | 165(112–237) | 132(81–203) | 158(86–203) | 0.14 |
| β2MG, mg/L | 27.0(23.9–29.2) | 25.0(22.0–27.0)a | 26.2(22.6–29.3) | 27.6(25.6–30.3)c | 0.009 |
| Kt/Vurea | 1.74(1.60–1.96) | 1.77(1.67–1.98) | 2.10(1.86–2.48)a,c | 1.95(1.71–2.21)a,b | <0.001 |
| Geriatric nutritional risk index | 99.7(94.6–106.8) | 96.5(91.0–101.5)a | 90.0(85.2–94.5)a,c | 87.7(82.6–91.6)a,c | <0.001 |
| hANP, pg/ml | 56.6(38.6–80.4) | 87.7(65.2–112.3)a | 65(42.1–95.5)c | 134.5(80.7–162.3)a,b | <0.001 |
| CTR in men (n=208), % | 49.7(46.2–52.5) | 51.6(47.6–54.8)a | 50.0(46.5–53.2) | 52.6(49.0–54.6)a | 0.039 |
| CTR in women(n=87), % | 51.6(49.5–53.5) | 52.3(48.6–56.8) | 54.2(50.4–54.6) | 56.6(52.2–59.2)a,c | 0.012 |
BMI, body mass index; BP, predialysis and postdialysis BP; CRP, C-reactive protein; CTR, cardiothoracic index; ECW/ICW, extracellular-to-intracellular water; hANP, postdialysis human atrial natriuretic peptide; iPTH, intact parathyroid hormone; Kt/V, single pool Kt/Vurea; SMI, skeletal muscle mass index; TC, total cholesterol; TG, triglyceride; β2MG, β2-microglobulin.
P < 0.05, compared with the normal skeletal muscle mass index group with extracellular-to-intracellular water ratio <0.66.
P < 0.05 compared with the low skeletal muscle mass index group with extracellular-to-intracellular water ratio <0.66.
P < 0.05, compared with the normal skeletal muscle mass index group without extracellular-to-intracellular water ratio <0.66.
Body Composition
As shown in Figure 1, both ICW and ECW were lower in patients with low SMI compared with those with normal SMI. Among patients with a high ECW/ICW ratio, the elevation of the ECW/ICW ratio was mainly attributable to lower ICW levels rather than marked ECW expansion. The results of a body composition analysis are presented in Tables 2 and 3, with the data stratified by gender. Similarly, when comparing patients with high versus low ECW/ICW ratios, the increase in the ECW/ICW ratio was primarily associated with lower ICW levels, while a slight increase or relative preservation of ECW was also observed, particularly in patients with low SMI. These patterns were consistent when expressed as absolute volumes or when indexed to body surface area (BSA).
Figure 1.
Body composition according to normal SMI group with or without ECW/ICW ratio <0.66 and low SMI group with or without ECW/ICW ratio <0.66. ECW/ICW, extracellular-to-intracellular water; SMI, skeletal muscle mass index.
Table 2.
Body composition in men according to normal skeletal muscle mass index group with or without extracellular and intracellular water ratio <0.66 and low skeletal muscle mass index group with or without extracellular and intracellular water ratio <0.66
| Patients Characteristics | Normal SMI Group, kg/m2 Men ≥7.0 (n=151, 72.6%) |
Low SMI Group, kg/m2 Men <7.0 (n=57, 27.4%) |
P for Overall Comparison | ||
|---|---|---|---|---|---|
| ECW/ICW <0.66 (n=115, 55.3%) | ECW/ICW ≥0.66 (n=36, 17.3%) | ECW/ICW <0.66 (n=35, 16.8%) | ECW/ICW ≥0.66 (n=22, 10.6%) | ||
| Body weight, kg | 68.5(62.7–78.3) | 63.9 (56.2–74.5) | 54.1(51.6–58.8)a,b | 51.2(46.8–54.9)a,b | <0.001 |
| BSA, m2 | 1.71(1.71–1.91) | 1.75 (1.62–1.90) | 1.58(1.53–1.66)a,b | 1.55(1.46–1.61)a,b | <0.001 |
| Total body water, L | 38.4(35.2–41.5) | 35.6 (33.9–40.1) | 30.6 (28.4–32.2)a,b | 30.7(28.2–32.2)a,b | <0.001 |
| Total body water, L per BSA | 21.3(20.6–22.5) | 21.4 (20.0–22.1) | 19.4(18.4–19.9)a,b | 19.4(18.7–20.1)a,b | <0.001 |
| ICW, L | 23.6(21.8–25.9) | 21.3(20.3–24.0)a | 18.8(17.3–19.7)a,b | 18.2(16.6–18.9)a,b | <0.001 |
| ICW, L per BSA | 13.2(12.6–14.0) | 12.8(11.9–13.1)a | 11.9(11.1–12.3)a,b | 11.5(11.2–11.9)a,b | <0.001 |
| Extracellular water, L | 14.5(13.4–15.9) | 14.7 (13.7–16.1) | 11.9(10.9–12.6)a,b | 12.5(11.6–13.2)a,b | <0.001 |
| Extracellular water, L per BSA | 8.2(7.8–8.5) | 8.6(8.1–8.9)a | 7.4(7.2–7.7)a,b | 7.9(7.7–8.2)b,c | <0.001 |
| Muscle, kg | 10.2(9.4–11.2) | 9.2(8.8–10.5)a | 8.1(7.5–8.6)a,b | 7.9(7.2–8.2)a,b | <0.001 |
| Muscle, kg per BSA | 5.7(5.5–6.0) | 5.5(5.1–5.7)a | 5.2(4.8–5.3)a,b | 5.0(4.8–5.2)a,b | <0.001 |
| Mineral, kg | 3.52(3.21–3.90) | 3.17(2.91–3.62)a | 2.79(2.59–2.95)a,b | 2.80(2.50–3.02)a,b | <0.001 |
| Mineral, kg per BSA | 1.95(1.86–2.10) | 1.88(1.72–1.99)a | 1.73(1.68–1.83)a,b | 1.78(1.72–1.96)a | <0.001 |
| Fat, kg | 17.8(11.3–23.0) | 16.2 (9.2–23.2) | 12.5(10.2–16.2)a | 9.9(4.7–13.9)a,b | <0.001 |
| Fat, kg per BSA | 9.5(6.8–12.0) | 9.3 (5.7–12.6) | 8.2 (6.5–10.0) | 6.8(3.5–8.8)a | 0.001 |
BSA, body surface area; ECW/ICW, extracellular-to-intracellular water; SMI, skeletal muscle mass index.
P < 0.05, compared with the normal skeletal muscle mass index group with extracellular-to-intracellular water ratio <0.66.
P < 0.05, compared with the normal skeletal muscle mass index group without extracellular-to-intracellular water ratio <0.66.
P < 0.05 compared with the low skeletal muscle mass index group with extracellular-to-intracellular water ratio <0.66.
Table 3.
Body composition in women according to normal skeletal muscle mass index group with or without extracellular and intracellular water ratio <0.66 and low skeletal muscle mass index group with or without extracellular and intracellular water ratio <0.66.
| Patients Characteristics | Normal SMI Group, kg/m2 Women ≥5.7 (n=51, 58.6%) |
Low SMI Group, kg/m2 Women <5.7 (n=36, 41.4%) |
P for Overall Comparison | ||
|---|---|---|---|---|---|
| ECW/ICW <0.66 (n=33, 38.0%) | ECW/ICW ≥0.66 (n=18, 20.7%) | ECW/ICW <0.66 (n=20, 23.0%) | ECW/ICW ≥0.66 (n=16, 18.4%) | ||
| Body weight, kg | 53.6(47.1–61.9) | 49.8(46.3–55.2) | 42.8(39.6–47.0)a,b | 42.6(39.6–46.8)a,b | <0.001 |
| BSA, m2 | 1.54(1.43–1.60) | 1.46(1.40–1.59) | 1.36(1.29–1.42)a,b | 1.34(1.30–1.40)a,b | <0.001 |
| Total body water, L | 27.2(25.8–29.1) | 26.6(25.4–28.6) | 23.2(21.9–24.1)a,b | 22.5(21.7–24.0)a,b | <0.001 |
| Total body water, L per BSA | 18.3(17.7–19.0) | 18.3(17.5–20.0) | 17.1(16.2–18.6)a,b | 16.7(16.0–17.7)a | <0.001 |
| Intracellular water, L | 16.7(16.2–17.9) | 15.8(15.3–17.2) | 14.2(13.6–14.8)a,b | 13.4(12.9–14.2)a,b | <0.001 |
| Intracellular water, L per BSA | 11.3(10.8–11.7) | 10.9(10.5–11.9) | 10.4(9.9–11.3)a | 10.0(9.5–10.5)a,b | <0.001 |
| Extracellular water, L | 10.5(10.0–11.3) | 10.7(10.2–11.8) | 9.1(8.4–9.4)a,b | 9.3(8.8–9.8)a,b | <0.001 |
| Extracellular water, L per BSA | 7.0(6.8–7.3) | 7.3(7.0–8.2) | 6.7(6.2–7.2)b | 6.9(6.5–7.3)b | <0.001 |
| Muscle, kg | 7.2(7.1–7.7) | 6.9(6.6–7.5) | 6.1(5.8–6.4)ab | 5.7(5.6–6.1)a,b | <0.001 |
| Muscle, kg per BSA | 4.9(4.7–5.1) | 4.7(4.5–5.1) | 4.5(4.3–4.9)a | 4.3(4.1–4.5)a,b | <0.001 |
| Mineral, kg | 2.62(2.46–2.81) | 2.64(2.48–2.81) | 2.28(2.20–2.45)a,b | 2.28(2.18–2.39)a,b | <0.001 |
| Mineral, kg per BSA | 1.77(1.66–1.87) | 1.80(1.70–2.01) | 1.70(1.57–1.87) | 1.67(1.60–1.82) | 0.23 |
| Fat, kg | 14.8(10.7–23.6) | 11.5(9.1–19.5) | 11.3(6.6–17.2) | 11.9(8.7–16.1) | 0.077 |
| Fat, kg per BSA | 9.9(7.2–15.0) | 7.9(5.8–13.1) | 8.1(5.3–12.2) | 8.9(6.6–12.0) | 0.27 |
BSA, body surface area; ECW/ICW, extracellular-to-intracellular water; SMI, skeletal muscle mass index.
P < 0.05, compared with the normal skeletal muscle mass index group with extracellular-to-intracellular water ratio <0.66.
bP < 0.05, compared with the normal skeletal muscle mass index group without extracellular-to-intracellular water ratio <0.66.
P < 0.05, compared with the low skeletal muscle mass index group with extracellular-to-intracellular water ratio <0.66.
In the normal SMI with high ECW/ICW group, ICW declined modestly in both sexes compared with those with a low ECW/ICW ratio, whereas ECW remained largely stable with only minimal variation. In men, ICW decreased from 23.6 to 21.3 L, while ECW changed only from 14.5 to 14.7 L. In women, ICW decreased from 16.7 to 15.8 L, with ECW shifting slightly from 10.5 to 10.7 L. BSA-indexed values showed the same pattern, with small reductions in ICW/BSA and negligible changes in ECW/BSA.
In the low SMI with high ECW/ICW group, reductions in ICW were more pronounced compared with those with a low ECW/ICW ratio; ECW tended to be preserved or slightly increased despite markedly lower muscle mass. In men, ICW declined from 18.8 to 18.2 L, whereas ECW increased from 11.9 to 12.5 L. Similarly, in women, ICW fell from 14.2 to 13.4 L, while ECW rose slightly from 9.1 to 9.3 L. BSA-indexed values mirrored these trends: ICW/BSA decreased in both sexes (men: 11.9→11.5; women: 10.4→10.0 L/m2), whereas ECW/BSA showed small but consistent increases (men: 7.4→7.9; women: 6.7→6.9 L/m2).
In the low SMI with high ECW/ICW group, reductions in ICW were more pronounced compared with those with a low ECW/ICW ratio; in contrast to the normal SMI group, ECW tended to be preserved or slightly increased despite markedly lower muscle mass. In men, ICW declined from 18.8 to 18.2 L, whereas ECW increased from 11.9 to 12.5 L. Similarly, in women, ICW fell from 14.2 to 13.4 L, while ECW rose slightly from 9.1 to 9.3 L. BSA-indexed values mirrored these trends: ICW/BSA decreased in both sexes (men: 11.9→11.5; women: 10.4→10.0 L/m2), whereas ECW/BSA showed small but consistent increases (men: 7.4→7.9; women: 6.7→6.9 L/m2).
The GNRI was significantly lower in the low SMI group compared with the normal SMI group (P < 0.001), whereas no significant differences were observed between patients with low and high ECW/ICW ratios within each SMI category (Figure 2).
Figure 2.
Association between SMI by ECW/ICW ratio and GNRI. GNRI, geriatric nutritional risk index.
Association between SMI by ECW/ICW Ratio and QoL
The mean scores of each SF-36 domain according to SMI and ECW/ICW ratio are summarized in Table 4 and illustrated in Figure 3. Patients in the Low SMI/High ECW/ICW group had significantly lower SF-36 scores, particularly in the domains of physical functioning, role limitations owing to physical health, bodily pain, general health, vitality, and role limitations owing to emotional health. Moreover, even within the normal SMI group, those with high ECW/ICW ratios demonstrated lower SF-36 scores than those with low ratios, indicating a further impairment in HRQoL.
Table 4.
Quality of life domains according to normal skeletal muscle mass index group with or without extracellular and intracellular water ratio <0.66 and low skeletal muscle mass index group with or without extracellular and intracellular water ratio <0.66
| QoL Domains | Normal SMI Group, kg/m2 Men ≥7.0 or Women ≥5.7 |
Low SMI Group, kg/m2 Men <7.0 or Women <5.7 |
P for Overall Comparison | ||
|---|---|---|---|---|---|
| ECW/ICW <0.66 (n=148) | ECW/ICW ≥0.66 (n=54) | ECW/ICW <0.66 (n=55) | ECW/ICW ≥0.66 (n=38) | ||
| Physical health domains | |||||
| Physical functioning | 85(70–95) | 65(45–75)a | 80(65–90)b | 55 (29–75)a,c | <0.001 |
| Role limitations caused by physical health problems | 100(25–100) | 25(0–75)a | 75(25–100)b | 0(0–75)a,c | <0.001 |
| Bodily pain | 79(55–100) | 55(33–72)a | 68(53–80)b | 60(44–88)a | <0.001 |
| General health | 50(35–55) | 40(30–50)a | 50(30–55) | 38(25–50)a,c | 0.004 |
| Mental health domains | |||||
| Vitality | 60(45–75) | 45(30–65)a | 55 (40–75) | 40(24–61)a,c | 0.006 |
| Social functioning | 88(63–100) | 63(50–100) | 75 (50–100) | 63(38–100)a | 0.063 |
| Role limitations caused by emotional health problems | 100(33–100) | 33(0–100)a | 100(33–100)b | 0(0–100)a,c | <0.001 |
| Emotional well-being | 72(60–84) | 64(48–84) | 68(56–84) | 62(44–77)a | 0.055 |
ECW/ICW, extracellular-to-intracellular water; QoL, quality of life; SMI, skeletal muscle mass index.
P < 0.05, compared with the normal skeletal muscle mass index group with extracellular-to-intracellular water ratio <0.66.
P < 0.05, compared with the normal skeletal muscle mass index group without extracellular-to-intracellular water ratio <0.66.
P < 0.05, compared with the low skeletal muscle mass index group with extracellular-to-intracellular water ratio <0.66.
Figure 3.
QoL domains according to normal SMI group with or without ECW/ICW ratio <0.66 and low SMI group with or without ECW/ICW ratio <0.66. QoL, quality of life.
Association between SMI-ECW/ICW Combinations and Mortality Risk
Among the 295 patients included in the analysis, 34 deaths occurred during the observation period. As shown in Figure 4, patients in the low SMI/high ECW/ICW group exhibited the poorest survival, whereas those with normal SMI and ECW/ICW ratios showed the most favorable outcomes. The cumulative mortality rates were 1.5, 3.2, 2.6, and 13.1 deaths per 100 patient-years in the normal SMI/normal ECW/ICW, normal SMI/high ECW/ICW, low SMI/normal ECW/ICW, and low SMI/high ECW/ICW groups, respectively.
Figure 4.
Kaplan-Meier survival curves stratified by SMI and ECW/ICW ratio. The cumulative mortality rates were 1.5, 3.2, 2.6, and 13.1 deaths per 100 patient-years for the normal SMI with normal ECW/ICW ratio, normal SMI with high ECW/ICW ratio, low SMI with normal ECW/ICW ratio, and low SMI with high ECW/ICW ratio groups, respectively.
Pairwise Cox comparisons among the four subgroups (Supplemental Table 1) demonstrated that the low SMI/high ECW/ICW group had a significantly higher mortality risk compared with the reference group (normal SMI/normal ECW/ICW), with an adjusted hazard ratio (HR) of 5.63 (95% confidence interval [CI], 2.09 to 15.15; Holm-adjusted P < 0.001). This high-risk group also had significantly worse survival than both the normal SMI/high ECW/ICW group (HR, 4.61; 95% CI, 1.67 to 12.71; adjusted P = 0.015) and the low SMI/normal ECW/ICW group (HR, 4.22; 95% CI, 1.40 to 12.68; adjusted P = 0.030). By contrast, none of the remaining comparisons among the other three groups reached statistical significance after multiple comparison adjustment (all adjusted P > 0.05).
ROC curve analysis showed that the area under the curve (AUC) for SMI in predicting mortality was 0.703 in men and 0.734 in women, with optimal cutoff values of 7.6 kg/m2 and 5.4 kg/m2, respectively. The AUC for the ECW/ICW ratio was 0.749, with an optimal cutoff value of 0.656, indicating that both indices demonstrate good discriminative ability for mortality risk.
Supplemental Table 2 presents the multivariable model without the interaction term. In this model, low SMI and high ECW/ICW remained significant predictors of mortality, whereas diabetes and log10 hANP were not significantly associated with risk. Table 5 presents the multivariable Cox model that included the interaction term between low SMI and high ECW/ICW. In this interaction model, both low SMI (HR, 2.63; 95% CI, 1.23 to 5.62; P = 0.013) and high ECW/ICW (HR, 2.49; 95% CI, 1.14 to 5.47; P = 0.023) were independently associated with mortality. The interaction term did not reach statistical significance (HR, 1.41; 95% CI, 0.98 to 2.09; P = 0.07), suggesting that no strong multiplicative synergy exists between the two factors. Importantly, the direction and magnitude of hazard ratios in the noninteraction model (Supplemental Table 2) were broadly consistent with those observed in the interaction model (Table 5), supporting the robustness of our findings (Table 6).
Table 5.
Multivariable Cox proportional hazards model including the interaction between low skeletal muscle mass index and high extracellular and intracellular water
| Variables | Multivariate Analysis | ||
|---|---|---|---|
| HR | 95% CI | P | |
| Age (per 1 yr) | 1.06 | (1.02 to 1.10) | <0.001 |
| Men (versus women) | 2.41 | (1.0 to 5.65) | 0.033 |
| Diabetes mellitus (yes versus no) | 1.41 | (0.70 to 2.84) | 0.33 |
| Log10 hANP | 1.78 | (0.36 to 8.77) | 0.48 |
| Low SMI group | 2.63 | (1.23 to 5.62) | 0.013 |
| High ECW/ICW ≥0.66 (yes versus no) | 2.49 | (1.14 to 5.47) | 0.023 |
| Interaction: low SMI×high ECW/ICW | 1.41 | (0.98 to 2.09) | 0.07 |
In the multivariable Cox model including an interaction term, both low skeletal muscle mass index (hazard ratio, 2.63; 95% confidence interval, 1.23 to 5.62; P = 0.013) and high extracellular-to-intracellular water (hazard ratio, 2.49; 95% confidence interval, 1.14 to 5.47; P = 0.023) were independently associated with mortality. The interaction between low skeletal muscle mass index and high extracellular-to-intracellular water did not reach statistical significance (hazard ratio, 1.41, 95% confidence interval, 0.98 to 2.09; P = 0.067), indicating no strong multiplicative synergy between the two factors. CI, confidence interval; ECW/ICW, extracellular-to-intracellular water; hANP, postdialysis human atrial natriuretic peptide; HR, hazard ratio; SMI, skeletal muscle mass index.
Table 6.
Hazard ratios of the low skeletal muscle mass index/high extracellular and intracellular water group in unadjusted, age-adjusted and gender-adjusted, and fully adjusted Cox models
| Variables | Multivariate Analysis | ||
|---|---|---|---|
| HR | 95% CI | P | |
| Unadjusted | 10.14 | (4.29 to 23.98) | 0.003 |
| Age-adjusted and gender-adjusted | 7.72 | (3.08 to 19.33) | <0.001 |
| Multivariable-adjusteda | 6.59 | (2.50 to 17.38) | <0.001 |
CI, confidence interval; HR, hazard ratio.
Adjusted for age, sex, diabetes mellitus, C-reactive protein, Log10 postdialysis human atrial natriuretic peptide.
Figure 5 illustrates the distribution of women (n=87) and men (n=208) according to SMI and ECW/ICW ratio. The color gradients depict patient density, and the values within each quadrant indicate the number and percentage of deaths together with the corresponding sample size (n). Mortality was highest among individuals with both low SMI and high ECW/ICW ratios, but patients with preserved SMI also exhibited increased mortality when the ECW/ICW ratio was elevated. These patterns highlight that body fluid imbalance confers prognostic risk independent of muscle mass, while the coexistence of low SMI and high ECW/ICW identifies the subgroup with the greatest vulnerability.
Figure 5.
Distribution of patients by sex according to SMI and ECW/ICW ratio. Kernel density shading represents patient density across the SMI and ECW/ICW spectrum for women (upper) and men (lower). Vertical and horizontal dotted lines indicate the cutoff values for low SMI and high ECW/ICW ratio. Each quadrant displays the number and percentage of deaths together with the total number of patients (n) within that category.
Discussion
In this multicenter cohort of patients undergoing maintenance hemodialysis, we found that reduced skeletal muscle mass and an elevated ECW/ICW ratio were independently associated with higher mortality. Patients exhibiting both abnormalities—low SMI and high ECW/ICW—had the greatest mortality risk, with adjusted hazard ratios exceeding five-fold compared with those who had preserved SMI and normal ECW/ICW ratios (Supplemental Tables 1 and 2). These results highlight the importance of evaluating skeletal muscle status and body fluid distribution concurrently rather than considering either factor in isolation.
The ECW/ICW ratio has traditionally been viewed as a marker of extracellular volume expansion driven by sodium retention. However, emerging evidence indicates that it also reflects intracellular volume loss associated with muscle atrophy, cellular shrinkage, and tissue-level deterioration. In our study, the ECW/ICW ratio demonstrated good discriminative ability for mortality (AUC 0.749), consistent with prior reports linking elevated ECW/ICW values to frailty, inflammation, and malnutrition in dialysis populations.13 Although we initially hypothesized that elevated ECW/ICW would primarily reflect disproportionate ICW loss, our findings suggest that both ICW depletion and modest ECW expansion contribute to this imbalance, particularly among individuals with low SMI. This pattern implies that sarcopenia may involve not only loss of contractile muscle mass but also expansion of the interstitial space due to fibrosis or reduced cellular density. In addition, undernourished or low body mass dialysis patients may struggle to achieve sufficiently low postdialysis target weights, resulting in residual extracellular fluid overload and a corresponding elevation in ECW/ICW.
The clinical profile of patients with high ECW/ICW ratios in our cohort—including increased natriuretic peptide levels and larger cardiothoracic ratios—supports a pathophysiologic link among muscle wasting, fluid overload, and cardiac stress.20–23 These features align with the malnutrition-inflammation-fluid overload syndrome, a condition characterized by chronic inflammation, nutritional deterioration, and extracellular volume expansion that can predispose patients to adverse cardiovascular events.11 Patients experiencing protein-energy wasting or cachexia may have diminished tolerance to volume overload,24,25 further accelerating fluid accumulation and heightening vulnerability to mortality. Together, these observations underscore the interconnected nature of muscle depletion, nutritional compromise, and impaired fluid homeostasis in hemodialysis patients.
The interaction between low SMI and high ECW/ICW did not reach statistical significance, suggesting that their combined effect on mortality is additive rather than multiplicative. Nevertheless, patients with both abnormalities consistently exhibited the worst survival outcomes, implying that reduced muscle mass and impaired muscle tissue integrity represent converging pathophysiologic pathways signaling heightened biologic frailty. The consistency of hazard ratios across interaction and noninteraction models further supports the robustness of this finding.
Beyond mortality, the combination of low SMI and high ECW/ICW was associated with poorer HRQoL, particularly in the physical functioning and role physical domains. This suggests that deterioration in both muscle quantity and tissue-level integrity may translate into meaningful limitations in daily activities. Although BIA does not assess muscle strength or physical performance—the core criteria for sarcopenia defined by Asian Working Group for Sarcopenia—a reduced SMI combined with an elevated ECW/ICW ratio may reflect impaired functional capacity of skeletal muscle, including decreased contractile efficiency, reduced intracellular hydration, and increased interstitial fibrosis. These biologic alterations could contribute to fatigue, reduced exercise tolerance, and mobility limitations frequently observed in frail hemodialysis patients. Thus, combining SMI with the ECW/ICW ratio may help identify individuals at risk for functional decline and diminished quality of life.
Several methodologic considerations warrant attention. First, BIA measurements were performed immediately after dialysis. This approach minimized confounding by interdialytic fluid accumulation but introduced the possibility that postdialysis fluid redistribution had not fully stabilized. Previous studies report mixed findings—some indicating that postdialysis measurements remain acceptably accurate, while others recommend a waiting period for more precise estimation.26 In routine clinical practice, however, prolonged postdialysis observation is burdensome; therefore, our approach represented a pragmatic compromise. The absence of predialysis or delayed postdialysis measurements limits the ability to fully evaluate dynamic fluid shifts. Second, the selection of 0.66 as the cutoff for the ECW/ICW ratio warrants clarification. Second, the selection of 0.66 as the ECW/ICW cutoff warrants consideration. Although this value aligns with previous studies in which elevated ECW/ICW ratios (0.57–0.66)13 consistently predicted mortality, inflammation, and protein-energy wasting, it also corresponds physiologically to the established ECW/TBW range in healthy adults (0.36–0.40),17,18 which mathematically equates to an ECW/ICW ratio near 0.66. Importantly, the ROC-derived optimal cutoff in our cohort was consistent with these previous findings, but external validation is needed to confirm its generalizability. Additional limitations include the relatively small number of deaths (n=34), which may have reduced statistical power to detect interaction effects, and the potential for residual confounding from comorbidities or inflammatory or nutritional factors. BIA cannot distinguish intracellular from interstitial fluid at the tissue level, and estimates may be influenced by hydration status or electrode placement. Finally, as this was an observational study conducted across four centers, causal inference is limited and generalizability may be constrained.
Despite these limitations, our findings have important clinical implications. Routine assessment of both SMI and ECW/ICW may help identify high-risk individuals who could benefit from targeted interventions such as resistance exercise, individualized nutritional support, anti-inflammatory strategies, or optimized fluid management. Incorporating these indicators into frailty or risk-stratification tools may enhance prognostic accuracy and support more personalized clinical decision-making.
In conclusion, low skeletal muscle mass and an elevated ECW/ICW ratio were independently associated with mortality in patients undergoing maintenance hemodialysis, and patients with both abnormalities demonstrated markedly higher risk. These findings underscore the prognostic relevance of evaluating both muscle quantity and tissue-level integrity using simple, noninvasive BIA-derived measurements and support their incorporation into routine clinical assessment.
Acknowledgments
The authors thank clinical engineers Ishimaru, Suzuki, Aoki, Enoki, and Uchino for their assistance with individualized body composition measurements.
Disclosures
Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B527.
Author Contributions
Conceptualization: Shingo Ishii, Yasushi Ohashi.
Data curation: Mai Hitaka, Shingo Ishii, Yasushi Ohashi, Yusuke Suzuki, Sadamu Takahashi, Tatsuki Tanaka, Keisuke Yamazaki, Norihito Yoshida.
Formal analysis: Mai Hitaka, Shingo Ishii, Yasushi Ohashi, Yusuke Suzuki, Sadamu Takahashi, Tatsuki Tanaka, Norihito Yoshida.
Funding acquisition: Yasushi Ohashi.
Investigation: Mai Hitaka, Shingo Ishii, Yasushi Ohashi, Yusuke Suzuki, Sadamu Takahashi, Tatsuki Tanaka, Keisuke Yamazaki, Norihito Yoshida.
Methodology: Yasushi Ohashi, Yosuke Yamada.
Project administration: Yasushi Ohashi.
Supervision: Motoyuki Masai, Yosuke Yamada, Keisuke Yamazaki.
Writing – original draft: Shingo Ishii.
Writing – review & editing: Yasushi Ohashi.
Funding
Y. Ohashi: Ministry of Education, Culture, Sports, Science and Technology (21K08289).
Declarative Statements
This study includes clinical experimentation and received Institutional Review Board or Ethics Committee approval. All patients provided written informed consent. This study includes clinical experimentation and complies with the Declaration of Helsinki. The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the Declaration of Istanbul on Organ Trafficking and Transplant Tourism.
Data Availability Statements
Original data generated for the study will be made available upon reasonable request to the corresponding author. Data Type: Observational Data. Reason for Restricted Access: This study involves clinical data obtained from hemodialysis patients, and the dataset contains sensitive health information governed by institutional ethics regulations. Although all data are de-identified, unrestricted public sharing is not permitted under the terms of our institutional review board approval. Therefore, the original data will be made available upon reasonable request to the corresponding author for research purposes, in accordance with ethical and privacy requirements.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/KN9/B528.
Supplemental Table 1. Pairwise comparisons of survival among the four SMI/ECWICW subgroups (Cox regression with Holm-adjusted P values).
Supplemental Table 2. Multivariable Cox proportional hazards model without the interaction term between low SMI and high ECW/ICW.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Original data generated for the study will be made available upon reasonable request to the corresponding author. Data Type: Observational Data. Reason for Restricted Access: This study involves clinical data obtained from hemodialysis patients, and the dataset contains sensitive health information governed by institutional ethics regulations. Although all data are de-identified, unrestricted public sharing is not permitted under the terms of our institutional review board approval. Therefore, the original data will be made available upon reasonable request to the corresponding author for research purposes, in accordance with ethical and privacy requirements.