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NDT Advance Access published online on April 3, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn053
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Body mass index, muscle and fat in chronic kidney disease: questions about survival

D. Mafra1, F. Guebre-Egziabher2 and D. Fouque2

1 Clinical Nutrition Department, Federal University Fluminense (UFF), Niterói, Brazil 2 Department of Nephrology, Hôpital E. Herriot and INSERM U870, University Lyon 1, F-69003, Lyon, France

Correspondence and offprint requests to: Denise Mafra, Clinical Nutrition Department, Federal University Fluminense (UFF), Niterói 24220-215, Brazil. E-mail: dmafra{at}terra.com.br, dmafra{at}vm.uff.br



   Abstract
Top
 Abstract
Introduction
 References
 
The human body can be roughly divided into two major compartments, fat mass and lean body mass. Adipose tissue is now considered to be a highly active tissue and, in addition to storing calories as triglycerides, it also secretes a large variety of compounds, including cytokines, chemokines and hormone-like factors such as leptin, adiponectin and resistin. On the other hand, muscle plays a central role in whole-body protein metabolism by serving as the principal provider for amino acids to maintain protein synthesis in vital tissues and organs and by providing hepatic gluconeogenic precursors. Although not a good indicator of body composition, the Quetelet index, also called body mass index (BMI), is often used for practical reasons. It is well known that high BMI predicts mortality and cardiovascular disease (CVD) in the general population. However, observational reports in the dialysis population have suggested that obesity is associated with improved survival, a phenomenon that is not well understood and subject to controversies. This review describes the characteristics of BMI in the general population and in chronic kidney disease (CKD) patients, as well as the respective role of muscle, whole body fat and fat distribution towards mortality, with particular emphasis on patients with CKD.

Keywords: BMI; haemodialysis; muscle mass; obesity; survival



   Introduction
Top
 Abstract
 Introduction
References
 
Although obesity confers an increased risk of mortality in the general population, observational reports in dialysis patients have suggested the opposite [1]. Adipose tissue is a complex organ with functions far beyond the mere storage of energy. It secretes a number of adipokines that are involved in the inflammatory process, and it has been proposed that adipose tissue may be a significant contributor to increased systemic and/or low-grade inflammation [2]. However, obesity in uraemic patients cannot be just estimated by high BMI, which does not differentiate muscle mass from adipose tissue. Researchers have shown that the protective effect conferred by high BMI seems limited to high muscle mass but not high fat mass. Despite a normal or high BMI, some patients also present the protein-energy wasting (PEW) syndrome, which includes low concentrations of visceral proteins (e.g. serum albumin and prealbumin) and loss of somatic protein stores (e.g. lean body mass) [3]. These patients have been reported to have a high mortality rate [4]. This review describes the characteristics of the BMI in the general population and in chronic kidney disease (CKD) patients, and the respective role of muscle and fat mass with respect to mortality.

BMI in the general population
According to WHO [5] and from large population-based studies from the Framingham database [6], the prevalence of overweight and obesity in adults has been increasing worldwide and an increment in BMI exponentially increases the risk of elevated blood pressure, high cholesterol and triglyceride levels, insulin resistance and subsequently the risk of coronary heart disease, heart failure, ischaemic stroke and type-2 diabetes. Thus, obesity predisposes individuals to a large number of comorbidities and increased mortality rates [7].

The body can be separated into tissue, organs and systems; thus, body weight is equal to adipose tissue + skeletal muscle + bone + blood + residual (visceral organs, etc.). According to WHO [7], body mass index (BMI) is a simple index of weight-for-height that is commonly used to classify underweight, overweight and obesity in adults. It is defined as the weight in kilograms divided by the square of the height in metre (kg/m2). Table 1 shows the classification of BMI.


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  		Table 1 The international classification of adult underweight, overweight and obesity according to BMI

 
Although BMI is often used as an indicator of nutritional status, it is not a good indicator of body composition, as it does not differentiate muscle from fat mass. BMI also does not reflect the most metabolically active compartments, i.e. muscle [8]. According to Cook et al. [9], the use of BMI in clinical practice may mask important changes in body composition and may result in a failure to detect nutritional impairment. The use of BMI has been identified as a barrier to completing the screening process at the ward level. Also, feedback from dieticians working with older subjects (>60 years of age) indicates that 72.5% of those using BMI express concerns that it is of limited use for practical reasons or that the reference range (20–25 kg/m2) is not appropriate for older subjects.

Indeed, BMI is not reliable in the elderly, because the body size, shape and composition vary with age and subjects tend to lose fat-free mass and increase fat mass. These changes may alter the functional significance of BMI at different ages [10]. Some authors have proposed that BMI thresholds should be modified for the elderly population, where a BMI <20 would classify elderly subjects as malnourished whereas a BMI between 25.0 and 29.9 kg/m2 should be considered desirable. Such a modification would result in many elderly currently classified as overweight being re-categorized as normal [11–12]. Some studies found a positive association between BMI and all-cause mortality in elderly [13–16]. For instance, Schooling et al. [16] observed that the effect of BMI on mortality in elderly varied with baseline health status, and that obese people had higher mortality.

In younger adults, recent epidemiological studies show comparable trends. A very large prospective study in the USA [17] showed that lowest rates of death from all causes were found at BMIs between 23.5 and 24.9 kg/m2 in men and 22.0 and 23.4 kg/m2 in women (Figure 1), and heavier men and women in all age groups had an increased risk of death. Interestingly, these authors showed that the association between BMI and the risk of death was substantially modified by smoking status, presence of disease and race. Among Caucasian subjects, those with the highest BMI had a higher relative risk (RR) of death as compared with those with a BMI of 23.5–24.9 kg/m2, and, conversely in Afro-American individuals, those with the highest BMI had much lower risks of death when compared with Caucasian people. Thus, more recent data and careful adjustment for covariates seem to reduce the predictive mortality value of BMI for values >25, whereas an increased mortality is constantly observed for BMI values <18–20.


Figure 1
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  		Fig. 1 Multivariate relative risk of death from cardiovascular disease, cancer, and all other causes among men and women who had never smoked and who had no history of disease at enrolment, according to body mass index. The reference category was made up of subjects with a body mass index of 23.5–24.9. N Engl J Med 1999; 341(15): 1097–1105. With permission from Massachusetts Medical Society.

 
Gerber et al. [18] recently showed how a J- or U-shaped curve may be obtained if careful analytical considerations of potential sources of bias were not done. They examined the association between BMI and all-cause mortality in more than 99 000 US males with a median follow-up of 5.7 years. A total of 5438 men died. A linear association was found between BMI and risk of death, even among those within the ‘overweight’ range of BMI without increased risk among the lean, when accounting for potential sources of bias. However, in the ‘optimal model’ when excluding men who died within 2 years and adjusting for age, smoking, alcohol consumption, physical activity and prior disease, those with a BMI <20.0 kg/m2 had an RR of death of 0.88 (e.g. a significant reduction in mortality), as compared to men with a BMI of 22.5–24.9 kg/m2. In contrast, men with a BMI of 30.0–34.9 kg/m2 had an RR of 1.45, and those with BMI >35.0 kg/m2 had an RR of 1.62. This study shows that although a high BMI is still associated with increased mortality, a careful analytical consideration may greatly attenuate the death risk among obese adults, previously reported in other studies.

The worse outcomes for cardiovascular and total mortality seen in the overweight and mildly obese groups could not be explained by adjustment for confounding factors, but rather by the lack of discriminatory power of BMI to differentiate between body fat and lean mass. BMI has a poor specificity for excess adiposity; in addition, it does not characterize excess centrally distributed obesity, which is more consistently associated with adverse effects on metabolism, dyslipidaemia and insulin resistance [19–20]. For example, in a recent study using data from the Dallas Heart Study [21], the association between specific obesity measures (i.e. BMI, waist circumference and waist-to-hip ratio) and prevalent atherosclerosis showed that the waist-to-hip ratio had a better discrimination power of atherosclerosis than BMI. It is conceivable that in the near future, waist circumference may become a much more reliable tool than BMI for assessing metabolic risk and cardiovascular events.

Although obese patients have worse outcomes than normal-weight patients, recent studies in patients with coronary artery disease [22], chronic heart failure or kidney disease have suggested that obesity may actually be associated with better outcomes, the so-called obesity paradox. This phenomenon is neither universally accepted nor completely understood [23] and because of this, further research is needed to know the benefits of losing weight or not. Thus, in non-CKD adults, the predictive value of BMI is still observed in the most recent observational reports. However, careful adjustments seem to reduce the importance of BMI as a cause of death in the general population.

BMI and the obesity paradox in chronic kidney disease
Given that diabetes and hypertension are the two most common causes of CKD, it is not surprising that excess weight is also present in CKD and end-stage renal disease (ESRD) (Figure 2). Several epidemiological investigations have confirmed that obesity is a significant risk factor for the appearance of proteinuria and ESRD in a normal population [24–27].


Figure 2
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  		Fig. 2 Adjusted relative risk for end-stage renal disease (ESRD) by body mass index (BMI). Model adjusted for multiphasic health checkup period, age, sex, race, education level, smoking status, history of myocardial infarction, serum cholesterol level, proteinuria, haematuria and serum creatinine level. Error bars represent 95% CI. Ann Intern Med. 2006; 144: 21–28. With permission from American College of Physicians.

 
Data are limited on the relationship of BMI to mortality in patients in the earlier stages of CKD, but Lo et al. [28] recently showed that greater BMI seems to be associated with lower HDL level in these patients. In addition, Caravaca et al. [29] showed that patients with CKD not yet on dialysis within the lowest and the highest quartiles of BMI had higher mortality than the rest of patients, but when patients without comorbidity were studied apart, only those with obesity showed worse survival, suggesting that obesity had a noteworthy impact on mortality in these patients.

At ESRD stage, the effect of overweight (BMI: 25– 30 kg/m2) or obesity (BMI: >30 kg/m2) has been repeatedly associated with improved survival whereas, in contrast, a BMI <19 kg/m2 was associated with increased mortality [30–34].

This situation is less clear in peritoneal dialysis (PD) patients, where studies have yielded mixed results [34–37]. MacDonald et al. [36] observed that obesity at the commencement of PD was a significant risk factor for death and technique failure. In contrast, according to Pliakogiannis et al. [37], high BMI patients should not be discouraged from PD just because of their size.

How to interpret the obesity paradox in dialysis?
A main drawback of BMI analysis is the comparison of short-term survival data from prevalent haemodialysis cohorts with a long-term J-shaped relation from the US general population since the long-term effect of BMI on mortality differs from its short-term effect [38]. In the general population, early mortality can be observed among lean individuals in a short period of follow-up [39], whereas obesity is associated with an increased mortality after an average follow-up of 12 years. De Mutsert et al. [40] recently examined the association of BMI with mortality in haemodialysis patients and in the general population, when age (50–75 years) and time of follow-up (7 years) were strictly comparable. They concluded that obesity (BMI >30 kg/m2) was associated with a non-protective hazard ratio of 1.2 (95% CI 0.8–1.7) in the haemodialysis population and 1.3 (95% CI 0.9–2.0) in the general population. In conclusion, a haemodialysis population and a general population with comparable age and equal duration of follow-up showed similar mortality risk patterns associated with BMI, thus questioning the reverse paradox.

Overall, in CKD patients, more attention should therefore be paid to patients who are underweight instead of overweight [40]. Weight loss as a consequence of disease may induce the early mortality associated with a low BMI [41]. It was shown that weight loss in the haemodialysis population is associated with increased cardiovascular and all-cause death [33]. The malnutrition-inflammation-cachexia syndrome has been proposed to explain the increased mortality risk of low BMI in the haemodialysis population [30,32], since most of low-BMI patients present symptoms of chronic inflammation.

Protective role of muscle in uraemic disease
Among all nutritional components, skeletal muscle protein, often represented by lean body mass, is of particular concern in patient morbidity and rehabilitation. Notably, there is a progressive decline of lean body mass in ESRD patients indicating on-going catabolism [4]. Interestingly, the mass of internal organ compartment that has been termed as ‘high metabolic rate compartment’ relative to body weight becomes lower as BMI increases, and this could contribute to lower uraemic toxin generation [8,42].

Preliminary data from a French prospective study confirmed the protective value of high BMI in 1345 haemodialyzed patients from the Regional Association of Nephrology but highlighted the fact that all BMIs in the same range were not equally protective, since only patients with a BMI > 25 and serum creatinine (SCr) >800 µmol/L had a lower mortality (annual mortality rate: 2%), whereas patients with SCr <800 µmol/L and BMI > 25 presented a higher mortality rate of 17% (Moreau-Gaudry et al., ASN 2007). Beddhu et al. [43], using 24-h urinary creatinine excretion, evaluated muscle mass in patients at the start of maintenance haemodialysis and showed that the protective effect conferred by a high BMI was also limited to those patients with normal or high muscle mass. Thus, it appears of importance in dialysis patients to report BMI with more information on body composition, using for instance easily available data such as predialysis creatinine.

Alterations in muscle function play an important role in most common diseases and conditions [44] and several studies in CKD patients have demonstrated that PEW (protein energy wasting) increases mortality and hospitalization [45,46]. The potential mechanisms by which CKD may negatively impact skeletal muscle are numerous, such as alteration in muscle perfusion and substrate delivery, catabolic state mediated by metabolic acidosis, corticosteroids, proinflammatory cytokines and decreased physical activity [47]. Adey et al. [48] reported that the rate of muscle protein synthesis was significantly lower in non-dialysed patients compared with healthy persons. In addition, haemodialysis has been shown to promote muscle as well as whole body protein catabolism [49] and, recently, creatinine index, used as a marker of muscle mass, showed that uraemic malnutrition constitutes an important risk factor for mortality in HD patients [50].

In a recent study, Honda et al. [51] showed that the commonly observed PEW was also present in overweight ESRD patients and this condition was associated with higher mortality; thus, BMI follow-up may be misleading as a single nutritional marker in ESRD patients and should be used concomitantly with other accepted parameters [3]. These data suggest that a good muscle mass confers a survival advantage in maintenance dialysis patients.

BMI, adipose tissue and inflammation
Adipose tissue is the body's largest energy repository and plays a double function crucial for energy homeostasis. On the one hand, it is the only organ suited to store triglycerides in highly specialized cells, e.g. adipocytes. On the other hand, the adipose tissue produces molecules, collectively named ‘adipokines’, that have recently been implicated in energy balance, glucose and lipid metabolism. The adipokines act locally, in an autocrine or paracrine manner, and distantly (endocrine), on various targets, including muscle, liver and the hypothalamus. Some adipokines, such as TNF-alpha and IL-6, promote insulin resistance and inflammation, whereas others like leptin and adiponectin are required for energy and glucose homeostasis [52].

In obesity, adipose cell hypertrophy and the recruitment of macrophages alter the secretory function and induce an inflammatory profile. The local and systemic consequences of interactions between macrophages and adipocytes are currently being actively studied, to understand their potential implication in the metabolic and cardiovascular complications associated with obesity [53,54].

Adipose tissue may be responsible for inflammatory burden. Adipokines and a ‘low-grade inflammatory state’ may be the link between the metabolic syndrome with its cluster of insulin resistance and cardiovascular diseases. In fact, atherosclerosis is now recognized as an ‘inflammatory’ process of the arterial wall [55]. Several studies have described an association between the visceral adipose tissue and carotid stiffness, this association being potentially mediated by circulating IL-6 and C-reactive protein (CRP) [56]. Visceral adipose tissue, in close association with the portal circulation, could be especially important in this pathway [47]. There is widespread support in the literature that central adiposity (fat in the trunk and/or abdomen) confers more cardiovascular risk than peripheral subcutaneous adiposity [57]. However, no study about differences between central or peripheral adiposity has been reported so far in haemodialysis patients. Axelsson et al. [58] showed that increasing fat mass in CKD patients was associated with increasing levels of sCD163, a circulating marker of macrophages associated with inflammatory process. Majchrzak et al. [4] showed that adiposity in CKD patients was associated with higher C-reactive protein and lower albumin levels. Haemodialysis patients with a high BMI may have increased risk for coronary heart disease, in support of an atherogenic role of fat tissue [59]. However, this may not be a common finding since Kalantar-Zadeh et al. showed no difference in inflammatory markers in four different BMI groups of haemodialysis patients [33].

Interestingly, fat mass (or a better body fat distribution) may become protective rather than deleterious in maintenance dialysis, and a reduction in fat mass over time seems to be associated with poor survival. In a 30-month longitudinal prospective study in 535 haemodialysis patients, low body fat was an independent risk factor of poor survival, even after adjustment for the fact that patients with higher body fat percentage were sicker and had a higher prevalence of diabetes and a prior history of cardiovascular disease than did patients with lower body fat. More importantly, a decrease in body fat over a 6-month period was associated with twice the death risk of those patients who had an increase in body fat [33]. Thus, opposite to the general population, in maintenance dialysis, fat mass appears to be protective and does not appear to be a strong determinant of chronic inflammation, underlining that fat is not all bad, and that fat distribution may potentially be the clue.

Questions about survival
In CKD, body composition in general and BMI in particular may be routinely puzzled by hydration disorders. Despite these limitations, epidemiological studies have shown that high BMI is protective in CKD patients. However, to clarify questions about BMI and survival, it is important to better quantify muscle mass and adipose tissue.

Is it muscle or fat that protects? The answer is probably both, but we still need larger prospective studies with detailed body composition analysis. Indeed, in most of the published studies, patient selection might have occurred, obese patients with low muscle mass should have died before ESRD, whereas obese patients with higher muscle mass should have survived. Secondly, high BMI patients may be protected from frequent catabolic illnesses by having greater energy stores.

Survival paradoxes have been mentioned for CKD, heart failure, obstructive lung disease, cancer, AIDS and rheumatoid arthritis, in the elderly, and may result from the time difference between two competing risk factors, i.e. over nutrition (long-term killer but short-term protective) versus under nutrition (short-term killer). For instance, studies in dialysis patients usually analyse patient survival between 2 and 5 years but no longer than this, and it seems necessary to extend studies for longer periods to clarify these issues [60].

In conclusion, in the general and maintenance dialysis population, recent analyses tend to limit the protective effect of high BMI on patient survival but underline new protective properties of specific body components, e.g. muscle mass or fat distribution. More detailed information on body composition should now be provided, such as lean body mass (i.e. SCr, anthropometry, DEXA, handgrip strength) and further studies are needed to examine the effects of lean body mass, fat mass and fat distribution, rather than BMI, on outcomes such as hospitalization or death. However, what remains without any doubt is the powerful mortality-predicting power of low BMI values, in the general population as well as in CKD patients, which should urge for urgent protein energy wasting (PEW) check-up and therapeutic interventions [3]. For this reason, the International Society for Renal Nutrition and Metabolism has recommended a BMI of <23 as a threshold for this PEW checkup in CKD patients [3].



   Acknowledgments
 
This study was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes)—Brazil.

Conflict of interest statement. None declared.



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Received for publication: 26. 9.07
Accepted in revised form: 23. 1.08


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The obesity epidemics in ESRD: from wasting to waist?
Nephrol. Dial. Transplant., February 1, 2009; 24(2): 376 - 380.
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