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original article
& 2006 International Society of Nephrology
Body fat mass and lean mass as predictors of survival in hemodialysis patients R Kakiya1, T Shoji2, Y Tsujimoto1, N Tatsumi2, S Hatsuda2, K Shinohara2, E Kimoto2, H Tahara2, H Koyama2, M Emoto2, E Ishimura3, T Miki4, T Tabata1 and Y Nishizawa2 1
Division of Internal Medicine, Inoue Hospital, Suita, Japan; 2Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan; 3Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan and 4Department of Geriatrics and Neurology, Osaka City University Medical School, Osaka, Japan
A higher body mass index (BMI) is a predictor of better survival in hemodialysis patients, although the relative importance of body fat and lean mass has not been examined in the dialysis population. We performed an observational cohort study in 808 patients with end-stage renal disease on maintenance hemodialysis. At baseline, fat mass was measured by dual-energy X-ray absorptiometry and expressed as fat mass index (FMI; kg/m2). Lean mass index (LMI) was defined as BMI minus FMI. During the mean follow-up period of 53 months, 147 deaths, including 62 cardiovascular (CV) and 85 non-CV fatal events, were recorded. In univariate analysis, LMI was not significantly associated with CV or non-CV death, whereas a higher FMI was predictive of lower risk for non-CV death. Analyses with multivariate Cox models, which took other confounding variables as covariates, indicated the independent associations between a higher LMI and a lower risk of CV death, as well as between a higher FMI and a lower risk of non-CV death. These results indicate that increased fat mass and lean mass were both conditions associated with better outcomes in the dialysis population. Kidney International (2006) 70, 549–556. doi:10.1038/sj.ki.5000331; published online 21 June 2006 KEYWORDS: body fat; lean mass; mortality; predictor; hemodialysis
Correspondence: T Shoji, Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail:
[email protected] Received 28 March 2005; revised 27 November 2005; accepted 13 December 2005; published online 21 June 2006 Kidney International (2006) 70, 549–556
Mortality rate is very high in patients with end-stage renal disease (or stage 5 chronic kidney disease) treated with hemodialysis, and the relative risk of death from cardiovascular (CV) events is 10–30 times higher in such patients as compared with the general population.1 The causes for the elevated death rate include multiple factors such as the presence of hypertension,2 hypotension,2,3 dyslipidemia,4,5 abnormalities in bone and mineral homeostasis,6,7 and impaired metabolism of carbohydrate and insulin resistance.8 In addition, atherosclerosis often coexists with inflammation and malnutrition in hemodialysis patients,9–11 and a low body mass index (BMI) and a low serum albumin level, the markers of malnutrition, are both predictors of poor survival in hemodialysis patients.12,13 Patients with advanced stages of chronic kidney disease suffer from protein-energy malnutrition.14 Protein-energy malnutrition can be defined as a state where net nutrient intake is lower than nutrient requirements, ultimately leading to various metabolic abnormalities, decreased tissue function, and loss of body mass.15 Body mass consists of fat mass and fat-free mass (lean mass). Lean mass can serve as an index of muscle mass and somatic protein storage, whereas fat mass more directly reflects energy storage. Therefore, reduction of BMI may indicate deteriorations in either of these two components of protein-energy malnutrition. Combe et al.16 reported no significant association between mortality risk and lean mass indirectly estimated from creatinine generation. In contrast, Arora et al.17 found that total body protein estimated as a nitrogen index by in vivo neutron activation analysis was predictive of death in a study of 76 hemodialysis patients. So far, however, there is no study in the literature that examined the relative importance of fat mass and lean mass in determining outcomes of patients on hemodialysis. In the present study, by using dual-energy X-ray absorptiometry (DEXA) that provides reliable information on body composition, we evaluated the differential contributions of fat mass and lean mass to outcomes in an observational cohort of hemodialysis patients. 549
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R Kakiya et al.: Body composition and survival of dialysis patients
RESULTS Body composition at baseline
the US (21.7%) dialysis patients in the dialysis outcomes and practice patterns study.18
Correlations of body composition with other variables at baseline
Table 2 shows the correlations of BMI, FMI, and LMI with other clinical data at baseline. BMI was correlated with dialysis duration (negatively) and serum creatinine (positively). FMI was correlated with systolic blood pressure (BP) (negatively), diastolic BP (negatively), and total cholesterol (positively). LMI was correlated with dialysis duration (negatively), systolic BP (positively), diastolic BP (positively), serum creatinine (positively), serum albumin (positively), and total cholesterol (negatively). As some of these correlations had only very low r-values, their clinical significance is unknown. Outcome of the subjects
16 r = 0.699 14 P < 0.0001 12 10 8 6 4 2 0 10 15 20 25 30 35 40 BMI (kg/m2)
LMI (kg /m2)
FMI (kg/m2)
During the mean follow-up period of 54 months, 147 patients died from CV (N ¼ 62) and non-CV (N ¼ 90) fatal events. CV deaths included deaths from ischemic heart disease (N ¼ 15), cerebrovascular disease (N ¼ 11), congestive heart failure (N ¼ 27), and sudden deaths (N ¼ 9). Non-CV causes consisted of infectious disease (N ¼ 24), cancer (N ¼ 20), hepatic cirrhosis (N ¼ 7), and others (N ¼ 34). The mortality rate of this cohort (4% per year) was lower than that of the Japanese (6.4%), the European (15.6%), and
Kaplan–Meier analyses
Kaplan–Meier analyses were performed to examine the univariate associations between body composition and outcomes of the cohort. Figure 2 gives the relationship between the BMI tertiles and the outcomes. Patients in the lowest tertile of BMI showed the highest risk of death from all causes (P ¼ 0.091). This was due to the elevated risk for non-CV disease (CVD) death (P ¼ 0.008) in the lowest BMI tertile. Figure 3 gives the Kaplan–Meier curves based on the FMI tertiles. Patients in the highest FMI tertile had the lowest risk for all-cause mortality, although it was not statistically significant (P ¼ 0.134). The patients in the highest FMI tertile showed a significantly reduced risk for non-CVD mortality (P ¼ 0.004). Similar analyses were performed for LMI (Figure 4), although no significant univariate association was found between the LMI tertiles and the risk of death from all-cause, CVD, or non-CVD events.
Table 1 | Baseline characteristics of the hemodialysis cohort Total number Gender (female:male) Diabetes (diabetes:non-diabetes) Age (years) Dialysis duration (months) Systolic BP (mm Hg) Diastolic BP (mm Hg) Creatinine (mg/dl) C-reactive protein (mg/dl) Albumin (g/dl) Total cholesterol (mg/dl) Albumin-corrected calcium phosphate (mg2/dl2) Hematocrit (%) BMI (kg/m2) FMI (kg/m2) LMI (kg/m2)
808 313:495 161:647 55.1711.4 70.1766.2 154721 81710 11.872.6 0.3 (0.05–10.5) 3.7870.36 164738 54.7713.4 28.774.2 20.772.9 4.672.3 16.172.1
The data are summarized as number, ratio, or mean7s.d. As C-reactive protein had a skewed distribution, the median (range) is given. BMI, body mass index; BP, blood pressure; FMI, fat mass index; LMI, lean mass index.
24 r = 0.594 22 P < 0.0001 20 18 16 14 12 10 8 10 15 20 25 30 35 40 BMI (kg/m2)
FMI (kg/m2)
BMI was positively correlated with fat mass index (FMI) (r ¼ 0.699, Po0.0001) and lean mass index (LMI) (r ¼ 0.594, Po0.0001), respectively, in the total subjects (Figure 1). The correlations of BMI with FMI and LMI were again significant when men (r ¼ 0.763 and 0.708, Po0.0001 for both) and women (r ¼ 0.863 and 0.588, Po0.0001 for both) were separately analyzed. However, a weak but statistically significant inverse correlation was found between FMI and LMI in the total subjects (r ¼ 0.160, Po0.0001). This may be due to a lower FMI (3.9271.88 vs 5.7472.53, Po0.001) and a higher LMI (17.0971.72 vs 14.5671.58, Po0.001) in men than in women. In fact, the inverse correlation was not confirmed when men (r ¼ 0.084, P ¼ 0.063) and women (r ¼ 0.100, P ¼ 0.078) were separately analyzed (for baseline characteristics of the subjects, see Table 1).
16 r = –0.160 14 P < 0.0001 12 10 8 6 4 2 0 8 10 12 14 16 18 20 22 24 LMI (kg/m2)
Figure 1 | Correlation between BMI, FMI, and LMI in the total subjects at baseline. 550
Kidney International (2006) 70, 549–556
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R Kakiya et al.: Body composition and survival of dialysis patients
Table 2 | Correlation between body composition and other clinical variables BMI
Age HD duration Systolic BP Diastolic BP Creatinine Albumin Cholesterol Calcium phosphate Hematocrit Log CRP
FMI
LMI
r
P
r
P
r
P
0.020 0.146 0.028 0.049 0.236 0.046 0.054 0.030 0.018 0.010
0.58 o0.01 0.44 0.17 o0.01 0.20 0.12 0.40 0.61 0.78
0.048 0.057 0.146 0.098 0.047 0.011 0.216 0.017 0.028 0.001
0.71 0.10 o0.01 o0.01 0.18 0.77 o0.01 0.63 0.43 0.98
0.081 0.137 0.201 0.177 0.379 0.074 0.167 0.022 0.007 0.012
0.02 o0.01 o0.01 o0.01 o0.01 0.04 o0.01 0.54 0.85 0.73
The table gives simple correlation coefficients (r-values) with level of significance (P-values). Calcium phosphate product was adjusted by serum albumin. BMI, body mass index; BP, blood pressure; CRP, C-reactive protein; FMI, fat mass index; HD, hemodialysis; LMI, lean mass index.
All-cause death P = 0.091
0.4
CVD death P = 0.873
Non-CVD death P = 0.008
BMI tertiles Lowest (12.3 – 19.3 kg/m2, N=269) Middle (19.3 – 21.7 kg/m2, N=270) Highest (21.7 – 35.8 kg/m2, N=269)
0.3 0.2 0.1 0.0
0.5 Cumulative incidence
Cumulative incidence
0.5
0.4 0.3
All-cause death P = 0.7889
CVD death P = 0.3843
Non-CVD death P = 0.7190
LMI tertiles Lowest (9.5 – 15.1 kg/m2, N =269) Middle (15.1 – 17.0 kg/m2, N =270) Highest (17.0 – 22.8 kg/m2, N =269)
0.2 0.1 0.0
0 20 40 60 80 100 0 20 40 60 80 0 20 40 60 80 Follow-up period (months)
0 20 40 60 80 100 0 20 40 60 80 0 20 40 60 80 Follow-up period (months)
Figure 2 | Survival curves of hemodialysis patients based on tertiles of BMI. The total cohort was divided into tertiles based on BMI, and survival curves were compared by the Kaplan–Meier analysis and log-rank test.
Figure 4 | Survival curves of hemodialysis patients based on tertiles of LMI. The total cohort was divided into tertiles based on LMI, and survival curves were compared by the Kaplan–Meier analysis and log-rank test.
Cumulative incidence
0.5
All-cause death P = 0.134
0.4
CVD death P = 0.565
Non-CVD death P = 0.004
FMI tertiles Lowest (0.8 – 3.3 kg/m2, N=269) Middle (3.3 – 5.3 kg/m2, N=269) Highest (5.3 – 15.0 kg/m2, N=270)
0.3 0.2 0.1 0.0
0 20 40 60 80 100 0 20 40 60 80 0 20 40 60 80 Follow-up period (months)
Figure 3 | Survival curves of hemodialysis patients based on tertiles of FMI. The total cohort was divided into tertiles based on FMI, and survival curves were compared by the Kaplan–Meier analysis and log-rank test.
Univariate analysis with Cox proportional hazards models
As the relationship between body composition and mortality rate is sometimes U-shaped, we checked for such a possibility with a Cox model, including BMI and BMI-squared as Kidney International (2006) 70, 549–556
covariates. BMI-squared was not significant, indicating no significant U-shaped relationship. In similar analyses with the pair of FMI and FMI-squared as well as LMI and LMIsquared, we again failed to find significant U-shaped relationship between the body composition indices and outcomes. Therefore, we did not include BMI-squared, FMIsquared, or LMI-squared terms for further analyses. Table 3 summarizes the univariate associations between the risk of death (all-cause, CVD, or non-CVD) and possible predictors, including BMI, FMI, and LMI. A higher BMI was predictive of a reduced risk for all-cause and non-CVD deaths. A higher FMI predicted a significantly reduced risk of non-CVD death, whereas it predicted an increased risk of CVD mortality at a borderline significance. LMI did not significantly predict all-cause, CVD, or non-CVD death. A higher age, the presence of diabetes mellitus, and a higher systolic BP were the significant predictors of an increased risk for all-cause mortality. This was also true for death from CVD and non-CVD. An elevated C-reactive protein (CRP) was a predictor of increased risk for all-cause mortality. Female gender, a higher serum albumin, and a higher creatinine were predictors for a reduced risk of all551
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R Kakiya et al.: Body composition and survival of dialysis patients
Table 3 | Univariate predictors of death in the hemodialysis cohort All-cause Age (per year) HD duration (per month) Gender (female vs male) Diabetes mellitus (vs non-diabtes) Systolic BP (per 1 mm Hg) Log CRP (per 1 log-unit) Albumin (per 1 g/dl) Total cholesterol (per 1 mg/dl) Calcium phosphate (per 1 mg2/dl2) Creatinine (per 1 mg/dl) BMI (per 1 kg/m2) FMI (per 1 kg/m2) LMI (per 1 kg/m2)
1.076*** 0.999 0.718* 3.792*** 1.015*** 1.484* 0.347*** 1.000 0.991 0.823*** 0.933* 0.937# 0.953
CVD
(1.061–1.092) (0.997–1.002) (0.515–0.999) (2.713–5.300) (1.007–1.023) (1.000–2.203) (0.221–0.547) (0.996–1.004) (0.979–1.003) (0.776–0.873) (0.881–0.989) (0.872–1.007) (0.883–1.029)
1.068*** 0.999 0.939 4.286*** 1.015* 1.448 0.607 1.006# 1.004 0.875** 1.012 1.089# 0.906
Non-CVD
(1.043–1.094) (0.995–1.003) (0.555–1.590) (2.503–7.339) (1.002–1.028) (0.768–2.729) (0.285–1.297) (1.000–1.012) (0.985–1.024) (0.793–0.964) (0.926–1.106) (0.985–1.203) (0.798–1.029)
1.081*** 1.000 0.607* 3.513*** 1.015** 1.508 0.250*** 0.996 0.983* 0.793*** 0.993*** 0.833*** 0.982
(1.062–1.101) (0.997–1.003) (0.395–0.932) (2.286–5.399) (1.004–1.025) (0.911–2.497) (0.142–0.441) (0.991–1.002) (0.967–0.999) (0.736–0.855) (0.821–0.955) (0.753–0.922) (0.892–1.081)
The table gives hazard ratios and 95% confidence intervals by univariate Cox proportional hazards model. Calcium phosphate product was adjusted by serum albumin. CRP (mg/dl) was log-transformed and entered into the model because of its skewed distribution. BMI, body mass index; BP, blood pressure; CRP, C-reactive protein; CVD, cardiovascular disease; FMI, fat mass index; HD, hemodialysis; LMI, lean mass index. # P=0.05–0.09, *Po0.05, **Po0.01, ***Po0.001.
Table 4 | Multivariate predictors of death in the hemodialysis cohort
Age (per year) HD duration (per month) Gender (female vs male) Diabetes mellitus (vs non-diabtes) Systolic BP (per 1 mm Hg) Log CRP (per 1 log-unit) Albumin (per 1 g/dl) Total cholesterol (per 1 mg/dl) Calcium phosphate (per 1 mg2/dl2) Creatinine (per 1 mg/dl) FMI (per 1 kg/m2) LMI (per 1 kg/m2) Global model significance
All-cause
CVD
Non-CVD
1.066*** (1.057–1.076) — — 2.727*** (2.270–3.274) — — 0.503** (0.391–0.648) — — 0.931* (0.897–0.966) 0.926* (0.891–0.962) —
1.060*** (1.045–1.075) — — 3.853*** (2.858–5.197) — — — — — — — 0.874* (0.814–0.938)
1.075*** (1.063–1.087) — — 2.459*** (1.943–3.114) — — 0.399** (0.291–0.546) 0.994* (0.991–0.997) — 0.880** (0.840–0.896) 0.850** (0.806–0.896) —
Po0.0001
Po0.0001
Po0.0001
The table gives hazard ratios by stepwise multivariate Cox analyses. Calcium phosphate product was adjusted by serum albumin. BP, blood pressure; CRP, C-reactive protein; CVD, cardiovascular disease; FMI, fat mass index; HD, hemodialysis; LMI, lean mass index. *Po0.05, **Po0.01, ***Po0.001.
cause and non-CVD deaths. A high total cholesterol level predicted an increased risk of CVD mortality at a borderline significance. An elevated calcium-phosphate product was a predictor of a reduced risk of non-CVD death. Multivariate analysis with Cox proportional hazards models
As the body composition indices were correlated with other clinical variables that were univariate predictors of outcome, we performed multivariate Cox analyses. In addition to FMI and LMI, the other 10 covariates in Table 3 were entered to the models, and independent associations with the outcomes were evaluated by a stepwise procedure. Table 4 summarizes the final results. The significant independent predictors for all-cause mortality were a higher age, the presence of diabetes mellitus, a reduced albumin, a low creatinine, and a reduced FMI. The significant independent predictors for CVD mortality were a higher age, the presence of diabetes mellitus, 552
and a reduced LMI. The significant independent predictors for non-CVD death were a higher age, the presence of diabetes mellitus, reduced serum levels of albumin, total cholesterol and creatinine, and a low FMI. Similar analyses were performed using the same multivariate models in which FMI and LMI were replaced with fat mass (kg), lean mass (kg), and height (m). We found a significant and independent association of fat mass with nonCVD mortality, but no significant association of lean mass with outcomes, suggesting that the effect of body composition on mortality is more sensitively detected by using FMI and LMI. As lean body mass is generally reduced in diabetic dialysis patients, but falsely increased in those with polycystic kidney disease, we confirmed the impacts of body composition in a subgroup of the cohort, excluding diabetic and polycystic kidney disease patients using the same multivariate Cox Kidney International (2006) 70, 549–556
R Kakiya et al.: Body composition and survival of dialysis patients
models shown in Table 4. The protective effect of FMI against non-CVD death was significant, whereas the effect of LMI on CVD death was not significant in this subpopulation. DISCUSSION
Protein-energy malnutrition is common among patients with advanced stages of chronic kidney disease.14 A higher BMI is an independent predictor of better survival in hemodialysis patients,12,13 although the relative importance of fat mass and lean mass remains unknown. In the present observational cohort study, we examined the outcome of hemodialysis patients in relation to their body composition by using DEXA, and found that a higher FMI was associated with a lower mortality rate, particularly that of non-CVD causes. Also, a higher LMI was an independent predictor for a lower risk of CVD death. This is the first study showing that both fat mass and lean mass are the important predictors of survival in hemodialysis patients. There is only one study19 in the literature that examined the relationship between DEXA-based body composition and the outcome of hemodialysis patients. Kato et al.19 showed that a lower ratio of limb/trunk lean mass by DEXA was a significant predictor of a higher risk of all-cause mortality in men, and that a lower percentage of fat content in the trunk was a significant predictor of death in women. Although they suggested the importance of regional body composition, their study did not answer which is more predictive of outcome of hemodialysis patients, total body fat mass, or lean mass. We tried to answer this question, and found that a higher FMI was an independent predictor of a lower risk of all-cause and non-CVD death, and that a higher LMI was an independent predictor of a lower risk of CVD mortality. The present results indicate that body fat has a protective role against death in the hemodialysis patients. This is in sharp contrast to the fact that increased body fat is an established risk factor of CVD and other health problems in the general population. Although we have no clear explanation for this apparent discrepancy, we speculate that adipose tissue has both potentially harmful and beneficial functions for health and survival, and that the beneficial functions may exceed the harmful effects in hemodialysis patients. The favorable actions of adipose tissue are presumably based on energy storage. When a patient is ill, due to infection, for example, he/she requires more energy to survive in the ill condition. Because fat is a more efficient source of energy than non-fat nutrients, it is conceivable that ill patients with greater fat mass have a better chance to survive. Indeed, a similar epidemiology between a higher BMI and a better survival is also known in some populations other than hemodialysis patients, such as the elderly individuals,20–23 patients with congestive heart failure,24 older women with cancer,25 and patients with lung cancer after surgery,26 although these studies did not directly measure body fat. We speculate that the beneficial effects of adipose tissue on survival are more apparent after the subjects become ill than before the subjects get the illness. Kidney International (2006) 70, 549–556
original article
Another explanation for the reverse epidemiology in hemodialysis patients is the possible changes in adipocyte functions in renal failure. As adipose tissue secretes both atherogenic and anti-atherogenic factors called adipocytokines, alterations in adipocytokine profile may affect the overall impact of adipocity on survival. Adiponectin is an adipocytokine having protective functions against atherosclerosis27–30 and insulin resistance.31 In the previous reports,27 adiponectin plasma level is lower in subjects with higher BMI. Zoccali et al.32 showed that hemodialysis patients have two to three times higher plasma adiponectin levels than the healthy controls, but that an increased adiponectin was the predictor of a lower risk for CVD events in hemodialysis patients. We recently showed that adiponectin in uremic plasma was apparently intact upon gel filtration and immunoblotting,33 and the inverse relationship between body fat and plasma adiponectin level was no longer significant in hemodialysis patients.34 In addition, the adiponectin/leptin ratio was significantly higher in the hemodialysis patients than that in the healthy control subjects,34 suggesting the alteration in plasma adipocytokine profile in the dialysis patients. The association between an increased LMI and reduced CVD death risk was not significant in univariate analyses, but it was significant only after adjustment for other confounding factors. We interpret these data to indicate that an increased muscle mass has a significant, but only minor influence on reduced risk for CVD death. An increased muscle mass is associated with physical activity and exercise training.35 Exercise can improve arterial stiffness in hemodialysis patients.36 Arterial stiffness is an independent predictor of CVD death in hemodialysis patients, as shown by us37 and others.38 In addition, although a recent study36 failed to detect such a beneficial metabolic effect of exercise in a small number of hemodialysis patients, exercise may improve insulin resistance in uremia, another independent predictor of CVD mortality in hemodialysis patients.8 Thus, the observed link between LMI and CVD death in hemodialysis patients may indicate the importance of physical activity and its metabolic effect in CVD. Kaizu et al.39 reported that Japanese hemodialysis patients showed a U-shaped association between BMI and mortality, and that those with BMI419.0 kg/m2 and those with BMIo16.9 kg/m2 had a higher risk of mortality than those with a BMI of 17.0–18.9 kg/m2. In contrast, we did not find the U-shaped association, but the inverse association between BMI and mortality in the 808 Japanese dialysis patients. Another study by Iseki et al.40 showed an inverse association between BMI and mortality in 1167 Japanese hemodialysis patients. Furthermore, the Japanese Society for Dialysis Therapy41 reported that mortality risk in 1 year showed an inverse association with BMI in 54 287 Japanese hemodialysis patients. Thus, the U-shaped association between BMI and mortality risk, reported by Kaizu et al., was not confirmed by these larger epidemiological studies in Japan. Although it is unknown what makes the results by Kaizu et al. different 553
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from other studies, the subject number, selection of the subjects, and follow-up period may have affected the results. Kaizu et al. enrolled 116 non-diabetic dialysis patients who already had survived the initial 2 years of hemodialysis at entry, and the follow-up period was 12 years. The other studies had a much larger number of subjects, and did not exclude those with diabetes mellitus or those having dialysis duration shorter than 2 years, but the follow-up periods were shorter than that of Kaizu et al. Wong et al.42 and Johansen et al.43 reported that Asians on hemodialysis in the US do not have better survival at higher BMI, and the U-shaped association was reported for Asian dialysis patients in the US.42 These results are in contrast to most of other studies from the US and European countries showing the survival advantage in obese or overweight dialysis patients,12,44–47 although a study from France16 did not find such a significant association. Although we cannot readily answer the reasons for the different epidemiology for Asians in the US, the difference in baseline BMI may affect the results. Asian dialysis patients including the Japanese are leaner than the other ethnic groups. Another explanation would be the difference in genetic background, lifestyle, and interaction of these factors. Asians tend to more easily develop diabetes mellitus when exposed to Western lifestyle at a lower BMI than the white,48 and it may cancel out the survival advantage in high-BMI categories. Taken together, most of these studies agree that a low BMI predicts poor survival of hemodialysis patients regardless of the different ethnic groups, and that most of the dialysis patients have a lower risk in high-BMI categories. However, the survival advantage in high-BMI categories may be cancelled out in the long run in a subgroup of patients who are more susceptible to obesity-related health problems. We found that FMI and LMI are differently correlated with other markers of nutrition, such as total cholesterol and serum albumin. Serum albumin and creatinine levels were correlated positively with LMI. Total cholesterol correlated positively with FMI, and negatively with LMI. These results indicate that fat mass and lean mass reflect the different aspects of protein-energy malnutrition in hemodialysis patients. Lean mass, serum albumin, and serum creatinine appear to form one group of markers for ‘protein malnutrition’, whereas fat mass and total cholesterol are in another group of markers for ‘energy malnutrition’ in the hemodialysis population. Malnutrition in the dialysis population often coexists with inflammation.9,11 However, in the present study, CRP was not significantly associated with FMI or LMI at baseline. Presumably, these indices of body composition can serve as the markers of nutritional status during a much longer term than the serum CRP, a marker of acute inflammation. In the present study, we showed negative correlations of hemodialysis duration with BMI and LMI, but not with FMI, suggesting that hemodialysis patients tend to lose their lean mass during long duration of dialysis. Similarly, aging is known to affect body composition. Lean mass decreases but 554
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fat mass increases during aging in the general population.49 Interestingly, in our previous studies,50,51 fat mass increased during the initial 3 years of hemodialysis treatment, but decreased thereafter. These studies indicate the difference in malnutrition found in aged people and long-term hemodialysis patients. There are several limitations in the present study. First, we did not collect data of non-fatal events, but only fatal events. Therefore, we were unable to separately analyze the risk factors of event occurrence and risk factors of fatality following the event.52 Second, because the number of deaths was relatively small, statistical power might not have been strong enough to detect the predictive ability of some risk factors such as serum albumin, CRP, and cholesterol in multivariate analyses. Also, we were unable to reliably perform subanalyses in men and women, or in diabetic and non-diabetic patients, because of the cohort size. Third, because we did not include data on history of previous CVD and medications, we cannot rule out the confounding effects of these factors. Fourth, because the hemodialysis patients in this cohort were selected on the basis of availability of DEXA scans, there may be a selection bias. Severely ill patients were possibly excluded, although DEXA scans were performed as one of the routine tests for renal bone disease. Fifth, the measurement of lean mass by DEXA may have overestimated the actual fat-free mass in some subjects. Excess body fluid would have increased the DEXA-measured ‘lean mass’. Although we tried to avoid such influence of fluid excess on lean mass by using ‘dry weight’ minus fat mass, the lean mass determined as such may still be inaccurate in patients with polycystic kidney disease. Finally, the present findings in the Japanese patients need to be confirmed in dialysis patients of other ethnicities. In conclusion, we showed that both body fat mass and lean mass were independent predictors of outcomes in the cohort of hemodialysis patients. Further studies are needed to clarify whether interventions to increase body fat and lean mass can reduce the risk of death in hemodialysis patients. MATERIALS AND METHODS Study design and subjects This is an observational study in a retrospective cohort consisting of 808 patients on maintenance hemodialysis in Inoue Hospital, Suita, Japan. The patients were selected from the entire patients of the dialysis center on the basis of availability of data of whole-body DEXA during the period between 1993 and 2000. The baseline data including serum biochemistry were collected in the same month when DEXA scans were performed. The clinical diagnoses of the primary renal disease were chronic glomerulonephritis (N ¼ 459), diabetic nephropathy (N ¼ 161), polycystic disease (N ¼ 45), hypertensive nephrosclerosis (N ¼ 27), toxemia of pregnancy (N ¼ 15), gout (N ¼ 13), lupus nephritis (N ¼ 8), and others/ unknown (N ¼ 80). The patients were dialyzed for 9–12 h per week using bicarbonate dialysate. Kt/V (1.4170.31, mean7s.d.) was available for 692 out of the 808 dialysis patients. The other baseline characteristics of the subjects are given in Table 1. The subjects were followed for a mean period of 54728 months, and the relationship Kidney International (2006) 70, 549–556
original article
R Kakiya et al.: Body composition and survival of dialysis patients
between the baseline data and outcomes was statistically analyzed. This study was approved by the ethical committee of the hospital. Measurement of body composition by DEXA Body weight in this study refers to ‘dry weight’. Body fat mass was measured by DEXA using a QDR-2000 (Hologic, Waltham, MA, USA) with the pre-installed software as described previously.53 Fatfree mass (lean mass) was calculated by subtracting fat mass from ‘dry weight’ to avoid the possible influence of body fluid excess on lean mass measured by DEXA. Previous studies54 reported that following one session of hemodialysis fat mass by DEXA did not change, whereas DEXA-measured lean mass excluding bone showed a significant decrease, as predicted by the body weight reduction by water removal. Body weight, fat mass, and lean mass (kg) were standardized by squared height (m2), and expressed in kg/m2 as BMI, FMI, and LMI, respectively.53 Biochemical assays and other measurements Blood samples were taken just before starting a dialysis session. Hematocrit, serum albumin, total cholesterol, and CRP levels were measured by routine laboratory methods. BP was measured at supine position before dialysis sessions, and the average of 12 measurements of the month was used for analysis. Statistical methods Data were summarized as mean7s.d. Difference in means between groups was evaluated by analysis of variance. As CRP did not have normal distribution it was summarized as median (range), and comparison among groups was made by Kruskal–Wallis test. Categorical data were presented as percentages and compared among groups by w2 test. Correlation was evaluated by simple linear regression analysis. BMI, FMI, and LMI were divided into tertiles, and survival curves were estimated by the Kaplan–Meier method and evaluated by log-rank test. Univariate and multivariate Cox proportional hazards models were used to calculate hazards ratios for possible predictors of outcomes. P-values of o0.05 were taken as statistically significant. All these calculations were performed by a Windows personal computer with statistics software StatView 5 (SAS Institute Inc., Cary, NC, USA). ACKNOWLEDGMENTS
We gratefully acknowledge the kind support by Narutoshi Odaka and Sugako Muro, and other staff at Inoue Hospital in collecting clinical and outcome data. Part of this study was presented at the Renal Week 2004 of the American Society of Nephrology in St Louis, Missouri in a preliminary form, and was published as an abstract. REFERENCES 1. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32: S112–S119. 2. Zager PG, Nikolic J, Brown RH et al. ‘U’ curve association of blood pressure and mortality in hemodialysis patients. Medical Directors of Dialysis Clinic, Inc. Kidney Int 1998; 54: 561–569. 3. Shoji T, Tsubakihara Y, Fujii M et al. Hemodialysis-associated hypotension as an independent risk factor for two-year mortality in hemodialysis patients. Kidney Int 2004; 66: 1212–1220. 4. Shoji T, Ishimura E, Inaba M et al. Atherogenic lipoproteins in end-stage renal disease. Am J Kidney Dis 2001; 38: S30–S33. 5. Nishizawa Y, Shoji T, Kakiya R et al. Non-high-density lipoprotein cholesterol (non-HDL-C) as a predictor of cardiovascular mortality in patients with end-stage renal disease. Kidney Int Suppl 2003; 63: S117–S120. 6. Block GA, Hulbert-Shearon TE, Levin NW et al. Association of serum phosphorus and calcium phosphate product with mortality risk in Kidney International (2006) 70, 549–556
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Kidney International (2006) 70, 549–556
