Literature DB >> 35749459

The association between body mass index and all-cause mortality in Japanese patients with incident hemodialysis.

Koji Inagaki1, Naoto Tawada1, Masahiro Takanashi1, Toshiyuki Akahori1.   

Abstract

BACKGROUND: A higher body mass index (BMI) has been associated with better survival among chronic kidney disease patients in some reports. However, more research is required to determine the associations between BMI and mortality in incident hemodialysis patients. Therefore, this study aimed to investigate the association between mortality and BMI measured at the first hemodialysis session and 2 weeks after hemodialysis initiation in Japanese patients with incident hemodialysis.
METHODS: We retrospectively enrolled 266 adult patients with incident hemodialysis who were treated at our hospital between May 2013 and June 2019. The data on BMI was obtained at the first hemodialysis session and 2 weeks after hemodialysis initiation. Patients were divided into tertiles based on BMI [<18.5 (low), 18.5-23.9 (normal), and ≥24 (high) kg/m2]. The normal group was used as the reference group. The primary outcome was all-cause mortality.
RESULTS: The mean age of patient was 68.9 ± 12.0 years, and the BMI was 23.3 ± 4.24 kg/m2 at the first hemodialysis session. The body mass index was 22.0 ± 3.80 kg/m2 at 2 weeks after hemodialysis initiation. During a mean follow-up of 3.89 ± 2.12 years, 80 (30.1%) deaths occurred. In multivariate analyses, low BMI at the first hemodialysis session was significantly associated with worse all-cause mortality (hazard ratio, 2.39; 95% confidence interval, 1.13-5.03). At 2 weeks after hemodialysis initiation, high BMI was significantly associated with better all-cause mortality (hazard ratio, 0.38; 95% confidence interval, 0.18-0.81).
CONCLUSION: At 2 weeks after HD initiation, high BMI was associated with lower mortality in Japanese patients with incident hemodialysis.

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Mesh：

Year:  2022        PMID： 35749459      PMCID： PMC9231701          DOI： 10.1371/journal.pone.0269849

Source DB:  PubMed          Journal:  PLoS One        ISSN： 1932-6203            Impact factor:   3.752


Introduction

Obesity is a major public health problem and is increasing worldwide [1]. Obesity is associated with a higher risk of diabetes, cardiovascular disease (CVD), and cancer, and an increased mortality in the general population [2, 3]. Obesity also increases the risk of chronic kidney disease (CKD) and its progression [4]. However, obesity is inversely associated with better survival among patients with chronic heart failure, chronic obstructive pulmonary disease and older age (i.e., elderly) [5-7]. This phenomenon is referred to as the “obesity paradox” [8]. Obesity appears to be associated with better survival among patients with pre-dialysis CKD and hemodialysis (HD) [9-11]. Among Japanese patients undergoing HD, low body mass index (BMI) at the start of HD was independently associated with an increased risk of all-cause death [12]. However, a higher BMI was not associated with a decreased risk of all-cause death. In addition, Johansen, et al. [13] reported that a high BMI at the beginning of dialysis was not associated with increased survival in Asian patients. Hoogeveen et al. [14] reported that BMI at the start of dialysis was not associated with mortality in elderly dialysis patients. We believe that this finding could be related to volume overload. Thus, we hypothesized if the effects of fluid overload were eliminated, high BMI patients would have a better prognosis. In the present study, we investigated the association between mortality and BMI measured at the first HD session and 2 weeks after HD initiation in Japanese patients with incident HD.

Materials and methods

Study design and participants

We conducted a retrospective cohort study in a single center. The participants were 284 patients, aged ≥20 years, who initiated maintenance HD from May 2013 to June 2019. Eighteen patients were excluded because the follow-up period was <3 months. Therefore, 266 patients were analyzed. This study was approved by the Ethics committee of Chutoen General Medical Center (Shizuoka, Japan). The approval number is KENI 139. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. The Ethics Committee approved a waiver of informed consent because this study was a retrospective study. Instead, we gave eligible patients the opportunity to opt out by posting a disclosure document on our institution’s website (https://www.chutoen-hp.shizuoka.jp/department/clinical-research/).

Clinical parameters

A diagnosis of “diabetes mellitus” (“DM”) was defined as a HbA1c levels ≥6.5% or treatment with antidiabetic medications. “Cardiovascular disease” (“CVD”) was defined as myocardial infarction, angina requiring percutaneous coronary intervention, hospitalization for heart failure, stroke, or peripheral artery disease requiring revascularization or amputation surgery. “Late referral” was defined as a referral to nephrologist <3 months before dialysis initiation. A temporary catheter was examined at the initiation of HD. An arteriovenous fistula (AVF) was examined at the time of decannulation of the temporal catheter. “Hypoxemia” was defined as a blood oxygen saturation of <90% or treatment with oxygen inhalation. Data on hypoxemia and pedal edema were obtained at the first HD session and 2 weeks after HD initiation. Blood pressure was measured before starting the dialysis. The cardiothoracic ratio was measured on x-ray images before starting the dialysis. The data on blood pressure and cardiothoracic ratio were obtained at the time of first HD session and 2 weeks after HD initiation. Blood tests were conducted on samples obtained at the first HD session and 2 weeks after HD initiation. We calculated the estimated glomerular filtration rate (eGFR) by using the modified equation for Japanese: [15]. The data of eGFR were obtained only at the first HD session to know the kidney function before HD initiation. Medication use referred to the drugs being taken at the first HD session.

BMI

The BMI was calculated based on body weight in kilograms divided by height in meters squared. Body weight was defined as ‘dry weight’ measured after HD session. The data on body weight was obtained at the first HD session and 2 weeks after HD initiation. This is because the state of overhydration was controlled by 2 weeks after HD initiation in most patients [16]. Patients were categorized into three groups: “high” was defined as a BMI ≥24 kg/m2; “normal,” as a BMI of 18.5–23.9 kg/m2; and “low,” as a BMI <18.5 kg/m2 [17].

Outcome

The primary outcome of our study was all-cause mortality. Patient survival was censored at kidney transplantation, loss to follow-up, or at the end of follow-up in February 2022.

Statistical analyses

Normally distributed variables are expressed as the mean ± the standard deviation (SD) and were compared by using analysis of variance (ANOVA). Nonparametric variables are expressed as the median and interquartile range (IQR) and were compared by using the Kruskal–Wallis test. Categorical variables are expressed as a number and proportion and were compared by using Fisher’s exact test. Kaplan–Meier analysis with log-rank tests was used for the survival analysis of three BMI categorical groups. We constructed Cox proportional hazards models to determine the risk of all-cause mortality associated with the BMI categories and clinical characteristics. Of the three BMI categorical groups, the normal group was used as the reference group. Model 1 was adjusted for age. Model 2 was adjusted for the variables in Model 1 plus sex and diabetes. Model 3 was adjusted for the variables in Model 2 with the addition of variables with p values < 0.05 in the univariate analysis. We also examined these relationships in the analysis of an elderly subgroup (≥65 years). The results are expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). All statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). EZR is a graphical user interface for R statistics (The R Foundation for Statistical Computing, Vienna, Austria) [18].

Results

Baseline characteristics

The patients’ characteristics are shown in Tables 1 and 2 at the first HD session and 2 weeks after HD initiation, respectively. The mean age was 68.9 ± 12.0 years, and 183 (68.8%) patients were elderly. Overall, 177 (66.5%) patients were male, 144 (54.1%) patients had a history of DM, and 83 (31.2%) patients had a history of CVD. The mean BMI at the first HD session was 23.3 ± 4.24 kg/m2. Overall, 96 (36.1%) patients were in the high BMI group, 148 (55.6%) patients were in the normal BMI group, and 22 (8.3%) patients were in the low BMI group. At 2 weeks after HD initiation, the mean BMI was 22.0 ± 3.80 kg/m2, 71 (26.7%) patients had high BMI, 146 (54.9%) patients had normal BMI, and 49 (18.4%) patients had low BMI groups. The number of patients with hypoxemia decreased from 45 (16.9%) patients at the first HD session to 3 (1.1%) patients at 2 weeks after HD initiation. The number of patients with pedal edema decreased from 155 (58.3%) patients at the first HD session to 34 (12.8%) patients at 2 weeks after HD initiation and that of patients with non-overhydration (no hypoxemia and no pedal edema) increased from 100 patients (37.6%) at the first HD session to 230 patients (86.5%) at 2 weeks after HD initiation. The mean sBP was 155.3 ± 27.6 mmHg at the first HD session and decreased to 146.4 ± 25.5 mmHg at 2 weeks after HD initiation. The mean cardiothoracic rate was 54.6 ± 6.98% at the first HD session and decreased to 52.4 ± 6.57% at 2 weeks after HD initiation.
Table 1

Baseline clinical characteristics in 266 patients at the first HD session.

BMI(The first HD session)
variablesAll(n = 266)≥24(n = 96)18.5–23.9(n = 148)<18.5(n = 22)P value
Age, years68.9 ± 12.062.7 ± 12.971.6 ± 10.076.9 ± 8.07<0.01
Elder (≥65 years)183 (68.8)50 (52.1)113 (76.4)20 (90.9)<0.01
Male/ Female177 (66.5)/ 89 (33.5)69 (71.9)/ 27 (28.1)97 (65.5)/ 51 (34.5)11 (50.0)/ 11 (50.0)0.14
Smoking history161 (60.5)63 (65.6)87 (58.8)11 (50.0)0.33
DM144 (54.1)64 (66.7)74 (50.0)6 (27.3)<0.01
CVD83 (31.2)25 (26.0)52 (35.1)6 (27.3)0.31
Late referral43 (16.2)15 (15.6)23 (15.5)5 (22.7)0.65
BMI (first HD session), kg/m223.3 ± 4.2427.8 ± 3.2821.3 ± 1.5717.3 ± 0.89<0.01
BMI (two weeks after HD initiation), kg/m222.0 ± 3.8025.9 ± 3.1020.2 ± 1.6016.9 ± 0.91<0.01
temporary catheter76 (28.6)27 (28.1)41 (27.7)8 (36.4)0.70
AVF235 (88.4)87 (90.6)132 (89.2)16 (72.7)0.071
Hypoxemia45 (16.9)16 (16.7)26 (17.6)3 (13.6)0.97
Pedal edema155 (58.3)66 (68.8)78 (52.7)11 (50.0)0.030
sBP, mmHg155.3 ± 27.6163.4 ± 26.8151.0 ± 26.4149.5 ± 32.0<0.01
dBP, mmHg79.4 ± 15.584.7 ± 16.276.5 ± 14.675.0 ± 13.3<0.01
Cardiothoracic rate, %54.6 ± 6.9855.3 ± 7.1554.2 ± 6.9154.5 ± 6.760.48
Hemoglobin, g/dL9.40 ± 1.519.37 ± 1.499.44 ± 1.539.25 ± 1.490.84
Albumin, g/dL3.07 ± 0.633.03 ± 0.693.07 ± 0.613.24 ± 0.420.38
Potassium, mEq/L4.46 ± 0.854.42 ± 0.804.50 ± 0.884.35 ± 0.850.62
Adjusted Ca, mg/dL8.77 ± 0.928.69 ± 0.888.79 ± 0.969.05 ± 0.760.25
P, mg/dL6.29 ± 1.696.49 ± 1.596.15 ± 1.746.40 ± 1.680.28
Cr, mg/dL9.11 [7.73–10.5]9.54 [8.41–11.1]8.82 [7.46–10.2]8.03[6.14–10.8]<0.01
eGFR, mL/min /1.73 m24.89 ± 1.554.76 ± 1.514.88 ± 1.415.54 ± 2.400.11
Use of RAASI143 (53.8)48 (50.0)84 (56.8)11 (50.0)0.55

Values are presented as mean (± SD), median [IQR], and Numbers (%). Abbreviations; HD, hemodialysis; BMI, body mass index; DM, diabetes mellitus; CVD, cardiovascular disease; AVF, Arteriovenous fistula; sBP, systolic blood pressure; dBP, diastolic blood pressure; Ca, calcium; P, phosphorus; Cr, creatine; eGFR, estimated glomerular filtration rate; RAASI, renin-angiotensin-aldosterone system inhibitor.

Table 2

Baseline clinical characteristics in 266 patients at 2 weeks after HD initiation.

BMI(Two weeks after HD initiation)
VariablesAll(n = 266)≥24(n = 71)18.5–23.9(n = 146)<18.5(n = 49)P value
Age, years68.9 ± 12.061.4 ± 12.770.1 ± 10.675.9 ± 9.05<0.01
Elder (≥65 years)183 (68.8)35 (49.3)105 (71.9)43 (87.8)<0.01
Male/ Female177 (66.5)/ 89 (33.5)48 (67.6)/ 23 (32.4)107 (73.3)/ 39 (26.7)22 (44.9)/ 27 (55.1)<0.01
Smoking history161 (60.5)46 (64.8)93 (63.7)22 (44.9)0.049
DM144 (54.1)49 (69.0)76 (52.1)19 (38.8)<0.01
CVD83 (31.2)15 (21.1)51 (34.9)17 (34.7)0.10
Late referral43 (16.2)10 (14.1)25 (17.1)8 (16.3)0.88
BMI (first HD session), kg/m223.3 ± 4.2428.6 ± 3.4322.4 ± 2.0418.5 ± 1.30<0.01
BMI (two weeks after HD initiation), kg/m222.0 ± 3.8027.1 ± 2.7621.0 ± 1.3917.4 ± 0.83<0.01
temporary catheter76 (28.6)20 (28.2)42 (28.8)14 (28.6)1.0
AVF235 (88.4)65 (91.5)130 (89.0)40 (81.6)0.23
Hypoxemia3 (1.1)0 (0.0)0 (0.0)3 (6.1)<0.01
Pedal edema34 (12.8)13 (18.3)18 (12.3)3 (6.1)0.15
sBP, mmHg146.4 ± 25.5151.5 ± 23.4144.7 ± 26.2144.1 ± 25.50.14
dBP, mmHg76.2 ± 13.480.8 ± 14.475.6 ± 13.171.6 ± 11.0<0.01
Cardiothoracic rate, %52.4 ± 6.5753.1 ± 7.3251.7 ± 6.3453.4 ± 5.970.19
Hemoglobin, g/dL9.58 ± 1.399.81 ± 1.419.59 ± 1.439.19 ± 1.150.051
Albumin, g/dL3.03 ± 0.593.16 ± 0.672.99 ± 0.572.94 ± 0.470.067
Potassium, mEq/L3.99 ± 0.544.14 ± 0.593.97 ± 0.503.86 ± 0.540.012
Adjusted Ca, mg/dL9.07 ± 0.609.09 ± 0.589.02 ± 0.649.18 ± 0.480.24
P, mg/dL4.66 ± 1.274.91 ± 1.684.62 ± 1.134.41 ± 0.870.086
Cr, mg/dL7.07 [5.96–8.58]8.02 [6.78–10.0]7.03 [6.02–8.40]5.97 [5.32–6.98]<0.01
eGFR, mL/min /1.73 m24.89 ± 1.554.72 ± 1.374.95 ± 1.524.97 ± 1.890.57
Use of RAASI143 (53.8)35 (49.3)78 (53.4)30 (61.2)0.44

Values are presented as mean (± SD), median [IQR], and Numbers (%). Abbreviations; HD, hemodialysis; BMI, body mass index; DM, diabetes mellitus; CVD, cardiovascular disease; AVF, Arteriovenous fistula; sBP, systolic blood pressure; dBP, diastolic blood pressure; Ca, calcium; P, phosphorus; Cr, creatine; eGFR, estimated glomerular filtration rate; RAASI, renin-angiotensin-aldosterone system inhibitor.

Values are presented as mean (± SD), median [IQR], and Numbers (%). Abbreviations; HD, hemodialysis; BMI, body mass index; DM, diabetes mellitus; CVD, cardiovascular disease; AVF, Arteriovenous fistula; sBP, systolic blood pressure; dBP, diastolic blood pressure; Ca, calcium; P, phosphorus; Cr, creatine; eGFR, estimated glomerular filtration rate; RAASI, renin-angiotensin-aldosterone system inhibitor. Values are presented as mean (± SD), median [IQR], and Numbers (%). Abbreviations; HD, hemodialysis; BMI, body mass index; DM, diabetes mellitus; CVD, cardiovascular disease; AVF, Arteriovenous fistula; sBP, systolic blood pressure; dBP, diastolic blood pressure; Ca, calcium; P, phosphorus; Cr, creatine; eGFR, estimated glomerular filtration rate; RAASI, renin-angiotensin-aldosterone system inhibitor. The characteristics of the three BMI categorical groups at the first HD session are shown in Table 1. Significant differences between the three groups were observed in age, history of DM, pedal edema, systolic blood pressure (sBP), diastolic blood pressure (dBP), and serum creatinine (Cr). The characteristics of the three BMI categorical groups at 2 weeks after HD initiation are shown in Table 2. Significant differences between the three groups were observed in age, sex, smoking history, history of DM, hypoxemia, dBP, serum potassium, and serum Cr.

Mortality

During a mean follow-up of 3.89 ± 2.12 years, 80 (30.1%) deaths occurred. Of the 80 deaths, 22 (27.5%) were due to cardiac disease, 20 (25.0%) were due to infectious disease, 12 (15.0%) were due to malignancy, 7 (8.8%) were due to stroke. The 1-year mortality rate was 5.8%, and 3-year mortality rate was 16.2%. Among 183 elderly dialysis patients, 70 (38.3%) deaths occurred. The 1-year mortality rate was 7.3% and the 3-year mortality rate was 21.1% in elderly dialysis patients. Fig 1 shows the Kaplan–Meier curves for the cumulative survival rates of the three BMI categorical groups in the first HD session and 2 weeks after HD initiation. At the first HD session, patients in low BMI group had significantly worse survival than did patients in the other two groups. The 3-year mortality rate was 10.5% in the high BMI, 16.4% in the normal group, and 40.4% in the low BMI group. However, at 2 weeks after HD initiation, patients in the high BMI group had significantly better survival than did patients in the other two groups. The 3-year mortality rate was 4.5% in the high BMI group, 17.7% in the normal group, and 28.5% in the low BMI groups.
Fig 1

Kaplan–Meier survival curve analyses of event-free survival, based on the BMI category.

a) The first HD session. b) Two weeks after HD initiation. Abbreviations; BMI; body mass index, HD; hemodialysis.

Kaplan–Meier survival curve analyses of event-free survival, based on the BMI category.

a) The first HD session. b) Two weeks after HD initiation. Abbreviations; BMI; body mass index, HD; hemodialysis.

HRs on univariate and multivariate analysis

In univariate Cox regression analysis, age, history of CVD, AVF, hypoxemia, sBP, eGFR, and BMI category were significantly associated with survival outcome at the first HD session. At 2 weeks after HD initiation, age, history of CVD, AVF, hypoxemia, sBP, albumin, cardiothoracic rate, eGFR and BMI category were found to be significantly associated with survival outcome in univariate Cox regression analysis. At the first HD session, high (HR, 0.49; 95% CI, 0.29–0.85) and low BMI (HR, 2.78; 95% CI, 1.51–5.15) were significantly associated with all-cause mortality. At 2 weeks after HD initiation, high (HR, 0.31; 95% CI, 0.15–0.63) and low BMI (HR, 1.74; 95% CI, 1.06–2.87) were significantly associated with all-cause mortality (Tables 3 and 4).
Table 3

Hazard ratio of BMI category by multivariate Cox regression analysis for all-cause mortality in all HD patients and elderly (≥65 years) HD patients at the first HD session.

VariablesAllHR (95% CI)ElderlyHR (95% CI)
Model 0
 High0.49 [0.29–0.85]0.54 [0.29–0.997]
 Normal1.0 (reference)1.0 (reference)
 Low2.78 [1.51–5.15]2.50 [1.34–4.67]
Model 1
 High0.69 [0.40–1.20]0.61 [0.32–1.14]
 Normal1.0 (reference)1.0 (reference)
 Low1.93 [1.03–3.62]1.97 [1.04–3.76]
Model 2
 High0.68 [0.39–1.18]0.60 [0.32–1.13]
 Normal1.0 (reference)1.0 (reference)
 Low2.35 [1.21–4.57]2.34 [1.18–4.64]
Model 3
 High0.72 [0.40–1.29]0.64 [0.33–1.24]
 Normal1.0 (reference)1.0 (reference)
 Low2.39 [1.13–5.03]2.35 [1.08–5.12]

Model 0: unadjusted, Model 1: adjusted age, Model 2: Adjusted for Model 1 plus sex and DM, Model 3: Adjusted for Model 2 plus CVD, AVF, hypoxemia, sBP, and eGFR. Abbreviations; BMI, body mass index; HD, hemodialysis; HR, hazard ratio; CI, confidence interval; DM, diabetes mellitus; CVD, cardiovascular disease; AVF, Arteriovenous fistula; sBP, systolic blood pressure; eGFR, estimated glomerular filtration rate.

Table 4

Hazard ratio of BMI category by multivariate Cox regression analysis for all-cause mortality in all HD patients and elderly (≥65 years) HD patients at 2 weeks after HD initiation.

VariablesAllHR (95% CI)ElderlyHR (95% CI)
Model 0
 High0.31 [0.15–0.63]0.23 [0.09–0.59]
 Normal1.0 (reference)1.0 (reference)
 Low1.74 [1.06–2.87]1.62 [0.96–2.71]
Model 1
 High0.39 [0.19–0.81]0.26 [0.10–0.65]
 Normal1.0 (reference)1.0 (reference)
 Low1.30 [0.78–2.17]1.31 [0.76–2.26]
Model 2
 High0.40 [0.19–0.82]0.26 [0.10–0.68]
 Normal1.0 (reference)1.0 (reference)
 Low1.44 [0.84–2.45]1.43 [0.82–2.51]
Model 3
 High0.38 [0.18–0.81]0.23 [0.09–0.61]
 Normal1.0 (reference)1.0 (reference)
 Low1,43 [0.81–2.53]1.46 [0.79–2.70]

Model 0: unadjusted, Model 1: adjusted age, Model 2: Adjusted for Model 1 plus sex and DM, Model 3: Adjusted for Model 2 plus CVD, AVF, hypoxemia, sBP, albumin, cardiothoracic rate, and eGFR. Abbreviations; BMI, body mass index; HD, hemodialysis; HR, hazard ratio; CI, confidence interval; DM, diabetes mellitus; CVD, cardiovascular disease; AVF, Arteriovenous fistula; sBP, systolic blood pressure; eGFR, estimated glomerular filtration rate.

Model 0: unadjusted, Model 1: adjusted age, Model 2: Adjusted for Model 1 plus sex and DM, Model 3: Adjusted for Model 2 plus CVD, AVF, hypoxemia, sBP, and eGFR. Abbreviations; BMI, body mass index; HD, hemodialysis; HR, hazard ratio; CI, confidence interval; DM, diabetes mellitus; CVD, cardiovascular disease; AVF, Arteriovenous fistula; sBP, systolic blood pressure; eGFR, estimated glomerular filtration rate. Model 0: unadjusted, Model 1: adjusted age, Model 2: Adjusted for Model 1 plus sex and DM, Model 3: Adjusted for Model 2 plus CVD, AVF, hypoxemia, sBP, albumin, cardiothoracic rate, and eGFR. Abbreviations; BMI, body mass index; HD, hemodialysis; HR, hazard ratio; CI, confidence interval; DM, diabetes mellitus; CVD, cardiovascular disease; AVF, Arteriovenous fistula; sBP, systolic blood pressure; eGFR, estimated glomerular filtration rate. We adjusted these statistics in Model 1 (i.e., age), Model 2 (i.e., Model 1 plus sex and DM), and Model 3 (i.e., Model 2 plus CVD, AVF, hypoxemia, sBP, and eGFR) (Table 3). In Models 1, 2, and 3, low BMI (Model 3; HR, 2.39; 95% CI, 1.13–5.03) was significantly associated with worse all-cause mortality at the first HD session. High BMI was not significantly associated with survival outcome in Models 1, 2, and 3 at the first HD session. Similarly, we adjusted these statistics in Model 1 (i.e., age), Model 2 (i.e., Model 1 plus sex and DM), and Model 3 (i.e., Model 2 plus CVD, AVF, hypoxemia, sBP, albumin, cardiothoracic rate, and eGFR) at 2 weeks after HD initiation (Table 4). At 2 weeks after HD initiation, high BMI (Model 3: HR, 0.38; 95% CI: 0.18–0.81) was significantly associated with better all-cause mortality in Models 1, 2, and 3. Low BMI was not significantly associated with survival outcome in Model 1, 2, and 3 at 2 weeks after HD initiation. In elderly (≥65 years old) patients, low BMI (Model 3: HR, 2.35; 95% CI:1.08–5.12) was also significantly associated with worse all-cause mortality at the first HD session (Table 3). At 2 weeks after HD initiation, high BMI (Model 3: HR, 0.23; 95% CI:0.09–0.61) was significantly associated with better all-cause mortality. The HRs of all-cause death in high BMI were lower in elderly patients at 2 weeks after HD initiation in Models 1, 2, and 3 (Table 4).

Discussion

In this study, we evaluated the association between BMI and all-cause mortality in Japanese patients with incident HD. We found that low BMI was associated with higher all-cause mortality at the first HD session. High BMI was not significantly associated with all-cause mortality at the first HD session; however, it was associated with lower all-cause mortality at 2 weeks after HD initiation. These associations were stronger in elderly HD patients. The higher mortality risk for low BMI patients at the start of dialysis is in keeping with the findings of other studies. De Mutsert et al. [19] reported that a low BMI (i.e., <18.5 kg/m2) was associated with higher mortality risk in Dutch dialysis patients. Toida et al. [12] reported that low BMI (i.e., <18.5 kg/m2) increased the risk of all-cause mortality in Japanese dialysis patients. Two reasons may explain why a lower BMI increases the risk of all-cause mortality. First, low BMI can result from low food intake due to poor appetite and dietary restrictions. HD patients with malnutrition have a lower BMI, which is associated with higher mortality [20]. In a Japanese nationwide cohort study, malnutrition has been reported as a risk factor for death in HD patients [21]. In our study, BMI decreased 2 weeks after HD initiation because the volume overload was corrected. Thus, the low BMI group at the first HD session was actually leaner. Second, patients with a low BMI are more likely to have a low muscle mass. Carrero et al. [22] reported that muscle atrophy was more prominent in patients with a lower BMI and was associated with higher mortality in HD patients. Zhang et al. [23] reported that frailty significantly increased the mortality risk in end-stage renal disease patients. Patel et al. [24] reported that serum creatine was a surrogate marker of muscle mass in HD patients. In this study, low BMI patients had a lower serum Cr at 2 weeks after HD session. Thus, their low muscle mass may have been associated with the low BMI. In contrast, low BMI at 2 weeks after HD initiation was not significantly associated with survival outcome in the multivariate analyses. We assumed that there was a large difference in lean body mass between low and normal BMI groups at HD initiation. However, there was a small difference in lean body mass between low and normal BMI groups at 2 weeks after HD initiation. Lean body mass is critical for skeletal muscle mass assessment [25]. Additionally, a low lean body mass is an independent risk factor for malnutrition [26]. Arase et al. [27] reported that a low lean body mass was associated with an increased risk for all-cause mortality in Japanese patients on maintenance HD. Out of 49 patients in the low BMI group at 2 weeks after HD initiation, 28 (57.1%) belonged to the normal BMI group at the first HD session. We speculated that these patients would not have been excessively restricted nutritionally before HD initiation. As a result, even if these patients had undergone dialysis for 2 weeks to correct their fluid overload, they would have lost little muscle mass. Therefore, future studies need to investigate lean body mass in incident HD patients. In our study, the association of higher BMI with lower death risk was more pronounced in elderly HD patients. Similarly, Nagai et al. [28] reported that a high BMI was associated with an improved all-cause mortality in elderly patients undergoing HD, but not in middle-aged patients undergoing HD, in Japan. We speculated that muscle and fat mass have a greater effect on mortality in elderly patients than in young patients. Liu et al. reported that lean body mass had a greater effect on all-cause mortality in older adults than in younger adults [29]. Additionally, there was a monotonic positive association of fat mass with all-cause mortality in younger participants, but an approximate J-shaped trend in older participants [29]. In this study, high BMI groups in elderly patients had a higher serum Cr at 2 weeks after HD session than the other two groups. Additionally, only one of the 35 elderly patients in high BMI groups had a BMI >30 kg/m2. We speculate that older patients with high BMI had adequate muscle and fat mass. Therefore, adequate nutrition and exercise are important in elderly patients with pre-dialysis CKD. This study had several limitations. First, because the study population was small, we could not completely adjust for known prognostic factors. In addition, some clinical factors result in wide CIs. Second, because this study was observational study, we could not rule out residual confounding factors. Third, BMI does not distinguish between fat and muscle mass. Thus, higher BMI may imply a high fat mass or a high muscle mass. BMI had been measured only at the time of HD initiation in incident HD patients in other studies [13, 30–32]. however, in the current study, the BMI was measured at the first HD session and 2 weeks after HD initiation. Measuring BMI at 2 weeks after HD initiation could eliminate the influence of volume overload. In addition, measuring the BMI twice could make clinicians aware of the change in BMI from the HD initiation period.

Conclusions

In conclusion, low BMI at the first HD session was associated with higher all-cause mortality. High BMI at 2 weeks after HD initiation was associated with lower all-cause mortality. This tendency was stronger in elderly HD patients. In Japanese patients with incident HD, adequate nutrition and physical activity might have improved the prognosis.

Anonymous data set of 266 patients.

(XLSX) Click here for additional data file. 21 Feb 2022
PONE-D-21-33831
The association between body mass index and all-cause mortality in Japanese patients with incident hemodialysis
PLOS ONE Dear Dr. Inagaki, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The reviewers commented favorably on your manuscript, but had some worthwhile suggestions. The authors should address the remaining issues. Please submit your revised manuscript by Apr 07 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:
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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2.  Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this informatio [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No ********** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ********** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ********** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Please find the attached the comments file. 1)The conclusions could not be drawn appropriately based on the data presented. 2)The method of data collection and statistical analysis are unclear. There are two baselines. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Sawako Kato [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Submitted filename: Review BMI in HD Inagaki.docx Click here for additional data file. 1 Apr 2022 Point-by-point responses to Reviewer’s comment We would like to thank the reviewers for the time and effort in reviewing our manuscript and providing comments and suggestions, which have considerably helped us improve our manuscript. We have answered each of your points below and hope that our responses and revisions address all your comments. Comment 1: Which BMI did use to divide patients into three groups, at the first time HD session or 2 weeks after? Or, did the authors conduct survival analysis on two types of patient groups one from the other divided into three BMI categories? Did the authors do one survival analysis based on the data sheet divided into three groups by the first time BMI and another survival analysis based on the data sheet divided into three by the BMI after 2 weeks? If so, the authors should indicate not only the baseline data after 2 weeks of dialysis (Table1), but also the data after the start of dialysis. And The two survival analyzes should have different observation periods of 14 days. In particular, They should confirm whether the baseline data changes or not, since it was mentioned that the number of people in the three groups differs depending on when BMI was measured. Response 1: All data except for BMI were obtained at the fist HD session, and we had included the data at the first HD session in Table 1 in the original version of the manuscript. We have added the baseline data from the first hemodialysis (HD) session in Table 1 in revised version of the manuscript. We searched clinical and laboratory data from 2 weeks after HD initiation and have added baseline data at 2 weeks after HD initiation in Table 2. We have also provided detailed definitions and measurements of the factors in the “Clinical parameters” section (from page 5 line 78 to page 6 line 99). We reconstructed Cox proportional hazards models to determine the risk of all-cause mortality associated with the BMI categories and clinical characteristics based on data in the first HD session and 2 weeks after HD initiation. As the result, univariate Cox regression analysis revealed that age, history of CVD, AVF, hypoxemia, sBP, albumin, cardiothoracic rate, eGFR and BMI category were significantly associated with survival outcome at 2 weeks after HD initiation. Because there were too many variables with p values <0.05 in the univariate analysis, we extended the observational period from August 2021 to February 2022. Five patients who were excluded due to the follow-up period being <3 months in the original version of the manuscript were added in the revised version because we were able to monitor them for >3 months. Based on this comment, data were added for six patients who died within 3 months. As a result, the number of patients increased from 255 in the original version of the paper to 266 in the revised version. Similarly, the number of deaths in patients increased from 68 in the original version of the paper to 80 in the revised version. In multivariate analyses, low BMI at the first hemodialysis session was significantly associated with worse all-cause mortality (hazard ratio, 2.39; 95% confidence interval, 1.13–5.03). At 2 weeks after the hemodialysis session, high BMI was significantly associated with better all-cause mortality (hazard ratio, 0.38; 95% confidence interval, 0.18–0.81) (from page 2 line 35 to page 3 line 39). In elderly (≥65 years) patients, low BMI (Model 3: HR, 2.35; 95% CI: 1.08–5.12) was also significantly associated with worse all-cause mortality at the first HD session. At 2 weeks after HD initiation, high BMI (Model 3: HR, 0.23; 95% CI: 0.09–0.61) was significantly associated with better all-cause mortality. Thus, the revised manuscript has similar results as the previous manuscript. We have described these results in HRs on univariate and multivariate analysis section (From page 16 line 200 to page 21 line 251). Comment 2: The authors stated that “the objective of the present study was to investigate the association between BMI and mortality in Japanese incident hemodialysis patients before and after the treatment of volume overload”. (line 66-68) and that “in our study, BMI decreased 2 weeks after HD initiation because the volume overload was corrected”. (line 246-247) . I agree that most patients probably improved their volume status. But, if they want to compare mortality between before and after the treatment of volume overload, they should evaluate and indicate data to support results that volume overload was corrected. �  Were all enrolled patients in condition with volume overload? They should indicate volume status at the first dialysis session. �  How many patients reached the adequate body weight after 2 weeks ultrafiltration treatment?. Response 2: To assess volume overload, pedal edema and hypoxemia has been added in the revised manuscript. At the first HD session, there were 45 (16.9%) patients with hypoxemia and 155 (58.3%) patients with pedal edema. At 2 weeks after HD initiation, there were three (1.1%) patients with hypoxemia and 34 (12.8%) patients with pedal edema. The number of patients with non-overhydration (no hypoxemia and no pedal edema) increased from 97 patients (36.5%) at the first HD session to 230 patients (86.5%) at 2 weeks after HD initiation. Therefore, we have added these results to the revised manuscript in the baseline characteristics section (From page 8 line 144 to page 9 line 154). Comment 3: The author should show the source to decide “BMI after 2 weeks treatment” Response 3: Based on your suggestion, we have added the following sentence “This is because the state of overhydration was controlled by 2 weeks after HD initiation in most patients [16]. (Page 6 line 103-104)” in the BMI section. The reference 16 has also been cited (from page 28 line 387 to 389). Comment 4: Also, the cardiothoracic ratio was relatively large in all groups in the data after 2 weeks of dialysis. They should show the data of cardiothoracic ratio decreased at the start of dialysis? Response 4: In the original version of the manuscript, cardiothoracic ratio was measured at the first HD session, as shown in Table 1. In the revised manuscript, cardiothoracic ratio in the first HD session has been included in Table 1, and the cardiothoracic ratio at 2 weeks after HD initiation has been included in Table 2. The mean cardiothoracic rate was 54.6 ± 6.98% at the first HD session and decreased to 52.4 ± 6.57% at 2 weeks after HD initiation We have added these values in the baseline characteristics section (from page 9 line 152 to page 153). Comment 5: Also, which body weight did they use to calculate BMI, before HD session or after HD session? We generally use body weight after HD session as dry weight = body weight without excess volume. Response 5: In this manuscript, we used body weight after HD session to calculate BMI. Thus, we have added a sentence “Body weight was defined as ‘dry weight’ measured after HD session.” (from page 6 line 102). . Comment 6: The authors used “BMI” and “overweight” as the same, but should use them separately. BMI is just a calculated number. High BMI include obesity, volume overload = overhydration, and overweight, and healthy with optimal weight, for instance high muscle mass. The unorganized and mixed terms makes readers confused. Response 6: According to your comment, we have modified the term “overweight” to “high BMI”. Similarly, we have modified the term “underweight” to “low BMI”. Comment 7: I could not catch what was the aim of this study. The authors stated that “The objective of the present study was to investigate the association between BMI and mortality in Japanese incident hemodialysis patients before and after the treatment of volume overload”. But they discussed only the association between BMI and mortality while they referred the previous reports. �  One clinical implication of this study may be that more attention should be paid to HD patients with low BMI because they are very likely in malnutrition status as compatible many previous reports. Weight loss as a consequence of disease including CKD may induce the early mortality associated with a low BMI. Another implication may be that some HD patients with low BMI could have hidden protein energy waste or frail. Response 7: We believe that the causes of poor prognosis in the low BMI group at the first HD session are malnutrition and frailty. Thus, we have added the following sentences: “In a Japanese nationwide cohort study, malnutrition has been reported as a risk factor for death in HD patients [21].” (from page 21 line 267 to line 268). We have also added “Zhang et al. [23] reported that frailty significantly increased the mortality risk in end-stage renal disease patients.” (from page 22 line 273 to line 274). Additionally, we changed the sentence “In Japanese patients with incident HD, adequate nutrition and physical activity might have improved the prognosis.” (from page 25 line 328 to line 330) in Conclusions section. Comment 8: And the authors should discuss why the association between low BMI after 2 weeks treatment and mortality disappeared. Response 8: We believe that this is because there are many patients who have lost weight by strictly restricting their diet for a short time. We have added the following sentence “On the other hand, low BMI at 2 weeks after HD initiation was not significantly associated with survival outcome in multivariate analyses. This is possibly because many patients who lost weight by strictly restricting their diet for a short time were included in this study. In CKD stage V patients, fluid overload, fatigue, and electrolyte abnormalities tended to occur because of decreasing urine production. Many patients prevent the occurrence of electrolyte abnormalities and overhydration by dietary restriction [25]. Therefore, it is necessary to investigate the changes in the type and quantity of food intake in pre-dialysis CKD patients in future studies.” (From page 22 line 278 to line 285) in the Discussion section. Comment 9: The authors should discuss the implication that association of higher BMI with lower death risk was more pronounced in elderly HD patients. Indeed, Japanese HD patients shows better survival that HD patients in Western countries. But it was not enough to explain the association of higher BMI with lower death risk. Response 9: We believe that the reason of association of higher BMI with lower death may be physical activity. Thus, we have added a sentence “In our study, the association of higher BMI with a lower mortality risk was more pronounced in elderly HD patients. Similarly, Oliva et al. [26] reported that high BMI was associated with decreased mortality in HD patients aged >75 years. We believe the reason for this is low physical activity. Inaguma et al. [27] reported that a low Barthel index, a measure of physical activity, was associated with a higher mortality risk in Japanese patients at HD initiation. In their study, the lower the Barthel index, the older the patient and the lower was the BMI.” (From page 23 line 287 to line 292) in the Discussion section. Comment 10: I guess that the best survival prospects for incident dialysis patients may be those who need not to lose weight after initiation dialysis therapy because euvolemia, and those who are gain body weight because less uremia. Alternatively, I also guess that if patients are suffer from heart failure, the patients with better cardiac function can remove water more. So the larger lose weight may be better prognosis in patients with heart failure. In this study, I would like to see the data of changes in body weight during the 2 weeks and the association between these change and mortality. Response 10: We calculated the difference in BMI at the first HD session and 2 weeks after the start of dialysis. The median BMI difference was 1 (IQR, 0.4-2.1). Then, we analyzed the differences in BMI by quartiles. The 3-year mortality rate was 10.9% in Q1, 13.6% in Q2, 18.3% in Q3, and 21.2% in Q4. However, it was not significant (p = 0.94) using Kaplan–Meier analysis with log-rank tests. Moreover, in univariate Cox regression analysis, the HRs in Q2, Q3, and Q4 were 1.07 [0.57-2.00], 0.90 [0.48-1.68], and 0.92 [0.48-1.77], respectively (The reference group was Q1). Comment 11: Six patients who died within three months were included as exclusion criteria. I think the main purpose of this study is to investigate the mortality of hemodialysis patients, so why did you exclude patients who died within 3 months? And was there any patients who died within 2 weeks? Response 11: All the six patients died between 2 weeks and 3 months after the start of dialysis. Because they had not been followed up for >3 months, the six dead patients were excluded in the original version of the manuscript. As the reviewer suggested, the six dead patients were included in the analysis in the revised manuscript. However, the addition of these six patients to the analysis did not change the results. Comment 12: The reference below (line 259-261) was not suitable for discussion about higher BMI with lower death risk. Add another proper one. �  Polinder-Bos et al. [22] reported that a lower BMI was associated with an increased 1-year mortality, but it was not associated with increased long-term mortality risk in elderly incident dialysis patients in the United States of America (USA). Response 12: Based on your comment, we have deleted the concerned sentence in the original version of the manuscript. Instead, we have added the following sentence “Similarly, Vashistha et al. [28] reported that high BMI (≥25 kg/m2) was not associated with lower mortality in HD patients aged >65 years.” (from page 23 line 297 to line 298) in the Discussion section. Comment 13: The authors had better show cause of deaths. Response 13: We have added the following sentence “Of the 80 deaths, 22 (27.5%) were due to cardiac disease, 20 (25.0%) were due to infectious disease, 12 (15.0%) were due to malignancy, 7 (8.8%) were due to stroke.” (Page 15 Line 181 to 183) in mortality section. Submitted filename: Response to reviewer.docx Click here for additional data file. 6 May 2022
PONE-D-21-33831R1
The association between body mass index and all-cause mortality in Japanese patients with incident hemodialysis
PLOS ONE Dear Dr. Inagaki, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The reviewers commented favorably on your manuscript, but had some worthwhile suggestions. The authors should address the remaining issues, including the discussion on potential mechanism. I am pleased to accept your manuscript, based on your revising it. Please submit your revised manuscript by Jun 20 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:
If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Michinari Nakamura, MD Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I would like to second review the manuscript submitted to Plos One by Koji Inagaki et al, Title; “The association between body mass index and all-cause mortality in Japanese patients with incident hemodialysis”. The manuscript has been much more improved than the previous one. I thank the authors for corrections. But there are still some concerns. Comment & Response 3: The authors should put the sentence “This is because the state of overhydration was controlled by 2 weeks after HD initiation in most patients [16] after the sentence “The data on body weight was obtained at the first HD session and 2 weeks after HD initiation.” Comment & Response 6: We still find the term “overweight” and “underweight” in the manuscript. Comment & response 8: The authors did not answer the question “why the association between low BMI after 2 weeks treatment and mortality disappeared” The patients number of low BMI was increased after 2 weeks after HD initiation. Perhaps, I suppose most patients who lost weight could not eat enough by anorexia by uremia and in part dietary restriction pre and post dialysis initiation. But, this does not explain the question. Comment & response 9: Same as Q8, the authors did not answer the question “why association of higher BMI with lower death risk was more pronounced in elderly HD patients” ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Sawako Kato [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.
27 May 2022 May 26, 2022 Michinari Nakamura, MD, PhD Academic Editor Plos One Dear Dr. Nakamura: We wish to re-submit the attached manuscript entitled “The association between body mass index and all-cause mortality in Japanese patients with incident hemodialysis”. The manuscript ID is PONE-D-21-33831R1. We thank you and the reviewer for your thoughtful suggestions and insights. The manuscript has benefited from these insightful suggestions. I look forward to working with you and the reviewer to move this manuscript closer to publication in the PLoS One. The manuscript has been rechecked and the necessary changes have been made in accordance with the reviewers’ suggestions. The responses to all comments have been prepared and attached. Thank you for your consideration. I look forward to hearing from you. Sincerely, Koji Inagaki Department of Nephrology, Chutoen General Medical Center, Shizuoka, Japan E-mail: koji-i@chutoen-hp.shizuoka.jp Point-by-point responses to Reviewer’s comment We appreciate the time and efforts of the reviewer in reviewing this manuscript again. We have addressed all issues in the review report and believed that the revised version now meets the journal publication requirements. Comment & Response 3: The authors should put the sentence “This is because the state of overhydration was controlled by 2 weeks after HD initiation in most patients [16] after the sentence “The data on body weight was obtained at the first HD session and 2 weeks after HD initiation.” Response: We appreciate the reviewer’s valuable comments. Accordingly, we have changed the sentence as follows: “The data on body weight was obtained at the first HD session and 2 weeks after HD initiation. This is because the state of overhydration was controlled by 2 weeks of HD initiation in most patients [16].” (page 6, lines 103–105). Comment & Response 6: We still find the term “overweight” and “underweight” in the manuscript. Response: We appreciate the reviewer’s careful observation and valuable comments on highlighting this issue. Accordingly, we have changed the terms “overweight” and “underweight” to “high BMI” and “low BMI,” respectively, in subsection “Mortality” of the “Results” section (page 15, lines 180–195). Comment & response 8: The authors did not answer the question “why the association between low BMI after 2 weeks treatment and mortality disappeared”. The patients number of low BMI was increased after 2 weeks after HD initiation. Perhaps, I suppose most patients who lost weight could not eat enough by anorexia by uremia and in part dietary restriction pre and post dialysis initiation. But, this does not explain the question. Response: We appreciate the reviewer’s valuable advice. We assumed that there was a large difference in lean body mass between low and normal BMI groups at HD initiation. However, there was a small difference in lean body mass between low and normal BMI groups at 2 weeks after HD initiation. Lean body mass is critical for skeletal muscle mass assessment [25]. Additionally, a low lean body mass is an independent risk factor for malnutrition [26]. Arase et al. [27] reported that a low lean body mass was associated with an increased risk for all-cause mortality in Japanese patients on maintenance HD. Out of 49 patients in the low BMI group at 2 weeks after HD initiation, 28 (57.1 %) belonged to the normal BMI group at the first HD session. We speculated that these patients would not have been excessively restricted nutritionally before HD initiation. As a result, even if these patients had undergone dialysis for 2 weeks to correct their fluid overload, they would have lost little muscle mass. Therefore, future studies need to investigate lean body mass in incident HD patients. We have added these sentences to our manuscript (page 22 line 279 to page 23 line 291) in the Discussion section. Comment & response 9: Same as Q8, the authors did not answer the question “why association of higher BMI with lower death risk was more pronounced in elderly HD patients” Response: We appreciate the reviewer’s valuable comment. We assumed that muscle and fat mass have a greater effect on mortality in elderly patients than in young patients. Thus, we revised the sentence as follows: “In our study, the association of higher BMI with lower death risk was more pronounced in elderly HD patients. Similarly, Nagai et al. [28] reported that a high BMI was associated with an improved all-cause mortality in elderly patients undergoing HD, but not in middle-aged patients undergoing HD, in Japan. We speculated that muscle and fat mass have a greater effect on mortality in elderly patients than in young patients. Liu et al. reported that lean body mass had a greater effect on all-cause mortality in older adults than in younger adults [29]. Additionally, there was a monotonic positive association of fat mass with all-cause mortality in younger participants, but an approximate J-shaped trend in older participants [29]. In this study, high BMI groups in elderly patients had a higher serum Cr at 2 weeks after HD session than the other two groups. Additionally, only one of the 35 elderly patients in high BMI groups had a BMI >30 kg/m2. We speculate that older patients with high BMI had adequate muscle and fat mass. Therefore, adequate nutrition and exercise are important in elderly patients with pre-dialysis CKD” (page 23 line 292 to page 24 line 305) in the Discussion section. Submitted filename: Response to reviewer.docx Click here for additional data file. 30 May 2022 The association between body mass index and all-cause mortality in Japanese patients with incident hemodialysis PONE-D-21-33831R2 Dear Dr. Inagaki, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Michinari Nakamura, MD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: 16 Jun 2022 PONE-D-21-33831R2 The association between body mass index and all-cause mortality in Japanese patients with incident hemodialysis Dear Dr. Inagaki: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Michinari Nakamura Academic Editor PLOS ONE
  32 in total

1.  Association between body mass index and mortality is similar in the hemodialysis population and the general population at high age and equal duration of follow-up.

Authors:  Renée de Mutsert; Marieke B Snijder; Femke van der Sman-de Beer; Jacob C Seidell; Elisabeth W Boeschoten; Raymond T Krediet; Jacqueline M Dekker; Jan P Vandenbroucke; Friedo W Dekker
Journal:  J Am Soc Nephrol       Date:  2007-01-31       Impact factor: 10.121

2.  Geriatric nutritional risk index accurately predicts cardiovascular mortality in incident hemodialysis patients.

Authors:  Hiroshi Takahashi; Yasuhiko Ito; Hideki Ishii; Toru Aoyama; Daisuke Kamoi; Hirotake Kasuga; Kaoru Yasuda; Shoichi Maruyama; Seiichi Matsuo; Toyoaki Murohara; Yukio Yuzawa
Journal:  J Cardiol       Date:  2013-12-22       Impact factor: 3.159

3.  Investigation of the freely available easy-to-use software 'EZR' for medical statistics.

Authors:  Y Kanda
Journal:  Bone Marrow Transplant       Date:  2012-12-03       Impact factor: 5.483

4.  Muscle atrophy, inflammation and clinical outcome in incident and prevalent dialysis patients.

Authors:  Juan Jesús Carrero; Michal Chmielewski; Jonas Axelsson; Sunna Snaedal; Olof Heimbürger; Peter Bárány; Mohamed E Suliman; Bengt Lindholm; Peter Stenvinkel; Abdul Rashid Qureshi
Journal:  Clin Nutr       Date:  2008-06-06       Impact factor: 7.324

5.  Frailty and mortality among patients with chronic kidney disease and end-stage renal disease: a systematic review and meta-analysis.

Authors:  Quanchao Zhang; Yingying Ma; Faying Lin; Jinghong Zhao; Jiachuan Xiong
Journal:  Int Urol Nephrol       Date:  2020-01-18       Impact factor: 2.370

6.  Body mass index and prognosis in patients with chronic heart failure: insights from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program.

Authors:  Satish Kenchaiah; Stuart J Pocock; Duolao Wang; Peter V Finn; Leonardo A M Zornoff; Hicham Skali; Marc A Pfeffer; Salim Yusuf; Karl Swedberg; Eric L Michelson; Christopher B Granger; John J V McMurray; Scott D Solomon
Journal:  Circulation       Date:  2007-07-16       Impact factor: 29.690

7.  Morbid obesity in Taiwan: Prevalence, trends, associated social demographics, and lifestyle factors.

Authors:  Heng-Cheng Chang; Hsin-Chou Yang; Hsing-Yi Chang; Chih-Jung Yeh; Hsin-Hung Chen; Kuo-Chin Huang; Wen-Harn Pan
Journal:  PLoS One       Date:  2017-02-02       Impact factor: 3.240

8.  Predicted lean body mass, fat mass, and all cause and cause specific mortality in men: prospective US cohort study.

Authors:  Dong Hoon Lee; NaNa Keum; Frank B Hu; E John Orav; Eric B Rimm; Walter C Willett; Edward L Giovannucci
Journal:  BMJ       Date:  2018-07-03

9.  Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents.

Authors:  Emanuele Di Angelantonio; Shilpa Bhupathiraju; David Wormser; Pei Gao; Stephen Kaptoge; Amy Berrington de Gonzalez; Benjamin Cairns; Rachel Huxley; Chandra Jackson; Grace Joshy; Sarah Lewington; JoAnn Manson; Neil Murphy; Alpa Patel; Jonathan Samet; Mark Woodward; Wei Zheng; Maigen Zhou; Narinder Bansal; Aurelio Barricarte; Brian Carter; James Cerhan; George Smith; Xianghua Fang; Oscar Franco; Jane Green; Jim Halsey; Janet Hildebrand; Keum Jung; Rosemary Korda; Dale McLerran; Steven Moore; Linda O'Keeffe; Ellie Paige; Anna Ramond; Gillian Reeves; Betsy Rolland; Carlotta Sacerdote; Naveed Sattar; Eleni Sofianopoulou; June Stevens; Michael Thun; Hirotsugu Ueshima; Ling Yang; Young Yun; Peter Willeit; Emily Banks; Valerie Beral; Zhengming Chen; Susan Gapstur; Marc Gunter; Patricia Hartge; Sun Jee; Tai-Hing Lam; Richard Peto; John Potter; Walter Willett; Simon Thompson; John Danesh; Frank Hu
Journal:  Lancet       Date:  2016-07-13       Impact factor: 79.321

10.  Predicted fat mass and lean mass in relation to all-cause and cause-specific mortality.

Authors:  Mengyi Liu; Zhuxian Zhang; Chun Zhou; Ziliang Ye; Panpan He; Yuanyuan Zhang; Huan Li; Chengzhang Liu; Xianhui Qin
Journal:  J Cachexia Sarcopenia Muscle       Date:  2022-01-23       Impact factor: 12.910
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