Department of Medicine, Nephrology Division, University of Mississippi Medical Center, Jackson, MS, USA
Keywords: BMI; dialysis; nutrition; obesity; risk factors; survival
Introduction
Factors associated with higher cardiovascular mortality in the general population may exhibit a paradoxical relationship with patients on dialysis. This dialysis-risk paradox has been reported for high blood pressure, serum lipids and body mass [111]. The finding, however, is more consistent and persuasive for obesity [47].
Relationship between body mass and survival on haemodialysis
The paradoxical observation of a lack of mortality increase with higher body mass index (BMI) in dialysis patients was first reported from France by the Diaphane collaborative study [12]. In 1998, Leavey et al. [13], while assessing the influence of a number of commonly used clinical parameters on dialysis survival, confirmed the association between low BMI and increased mortality in patients on haemodialysis. They also reported an absence of mortality risk in patients with higher BMI values. However, a study by our group, published in 1999, identified for the first time a significantly higher survival advantage for overweight and obesity in patients on haemodialysis [4]. This study, in which survival was evaluated prospectively, was based on a cohort of 1300 patients undergoing outpatient haemodialysis. The unexpected finding in this study was that overweight and obese patients (BMI of ≥27.5) had a significantly better 12-month survival than underweight (BMI <20) and normal weight (BMI of 2027.5) patients. Further analysis of the data, using Cox proportional hazard models, demonstrated that for every unit increase in BMI the relative risk (RR) of mortality was reduced by 10%. In multivariate analyses, higher BMI remained as a significant factor for better survival even after adjusting it for a number of variables commonly linked to dialysis patient's survival. In addition to reduced mortality, overweight patients compared to underweight patients had a significantly lower rate of hospital admissions and lower duration of hospital stay. This rather unexpected and paradoxical finding prompted an accompanying editorial titled Obesity and mortality in ESRD: is it good to be fat? [14]. Although provocative, our study had a number of limitations, such as the observational nature of the study and the predominance of African-Americans in the population. However, a number of subsequent studies, discussed below, support the association between high BMI and better survival on haemodialysis.
The influence of nutritional and physical parameters on survival was determined in 12 965 patients on haemodialysis by Kopple et al. [5]. They reported a weight-for-height dependent decrement in mortality rate; with the lowest mortality rates observed in patients who weighed more than the normal. In another study by Wolfe et al. [15] on a national US random sample from US Renal Data System, body size in various forms of measurement such as body weight, body volume, and body mass index was demonstrated to be independently and significantly correlated with better survival including those who were overweight and obese. Confirmation for a clear association between higher BMI and better survival comes from the recent work of Leavey et al. [6]. This study, based on a large pool of prospective data from Dialysis Outcomes and Practice Patterns Study (DOPPS) on nearly 10 000 haemodialysis patients from both Europe and US, reported a significantly lower relative mortality risk (RR) in overweight patients vs normal weight patients. Specifically, compared with patients of normal body weight, the relative risk for mortality was lower in overweight (RR of 0.84) and obese patients (RR of <0.76). Furthermore, this paradoxical BMIsurvival relationship was demonstrable in a wide variety of subgroups of haemodialysis patients on both sides of Atlantic, irrespective of variable baseline health status. Port et al. [7] in another large haemodialysis population reaffirmed the association between BMI and survival: patients with the lowest BMI had a 42% higher mortality risk than patients in the highest BMI tertile that included overweight and obese patients.
While the majority of the studies so far have found a positive association between body mass and survival on dialysis, a few studies have not. In a study by Kaizu et al. [16] of 116 patients from Japan, followed up on haemodialysis for nearly 12 years in the early 1980s, a BMI of more than 23.0 showed lowered survival rates compared to the patients with BMI of 17.018.9. In this study, survival on dialysis was also associated with a significant loss in BMI. A preliminary analysis from our group suggests that loss of body mass even in obese patients might portend a higher mortality [17]. Although limited in patients, Kaizu et al. [16] provided one of the longest follow up periods. It is, thus, possible that obese patients may have better survival in the short, but not necessarily in the long term. Furthermore, Japanese patients historically have had a lower mortality rate on dialysis compared to European or US patients. This, coupled with a lower prevalence of obesity, may require much larger patient populations than Kaizu et al. [16] to negate any obesity-survival advantage among the Japanese. Alternatively, race may confound the effect of obesity on survival, and unlike African Americans in whom obesity and higher survival on dialysis is strongly associated, obesity may herald a detrimental effect on the Japanese patients. Further studies on the effect of BMI on Japanese dialysis patients are required to clarify this issue. In a recent study from France, Combe et al. [18] did not find any influence of BMI on the 2-year survival of a cohort of 1610 haemodialysis patients. The mean BMI in this population was 23, substantially lower than that reported in US dialysis population. Therefore, this study might not have had the appropriate patient population to test the hypothesis of whether obesity is associated with better survival or not. The Spanish Cooperative Study of Nutrition in Haemodialysis is yet another study from Europe that assessed the relationship between survival and nutritional status [19]. Malnutrition was present in nearly 50% of their 761 haemodialysis patients and many suffered from protein-calorie malnutrition and fat depletion. Not surprisingly, an association was not found between excess body mass and survival in this population.
Relationship between body mass and survival on peritoneal dialysis
While the link between higher body mass and better survival is strong in haemodialysis patients, whether the same relationship exists in patients on peritoneal dialysis (PD) is not clear at the present time. Studies by Johnson et al. [20] and Aslam et al. [21] specifically addressed this issue, but arrived at differing conclusions. In the former study, overweight PD patients had a significantly better survival (71%) at 3 years compared to normal-weight patients (31%), possibly due to a significantly higher nutrition among the overweight patients. However, in the study by Aslam et al., no survival advantage was reported in the overweight patients. As in the Johnson et al. study, patients were divided into normal weight (BMI 2027.5) or obese (>27.5) in the Aslam et al. study. Over a 2-year period, obese patients had fewer deaths compared to normal-weight patients; the difference, however, did not reach statistical significance. Since the Aslam et al. study included a relatively small number of patients compared to larger numbers examined in haemodialysis studies, and the Johnson et al. study in PD patients reported a survival advantage in obese PD patients, it has been suggested that a conclusion of lack of association in the PD patients based on the Aslam et al. study alone might be premature [22]. Notably all the PD studies, including the large ADEMEX trial [23], which was designed to test the effect of peritoneal clearance on survival and not intended to study the relationship between body mass and survival, did not report any increased risk of death in overweight, obese patients on PD.
Body mass, race and dialysis doses
Two additional and potentially confounding issues, namely dialysis dose and patient race, need to be considered when one examines the effect of body mass on dialysis patients' survival. Several studies have shown that with standard prescriptions of dialysis, the delivered dose of dialysis (URR or Kt/V) is inversely related to body size [7,24,25]. This is not surprising given that V, the volume of distribution of toxins, is both a function of body size and also the denominator in Kt/V calculation of dialysis dose. Therefore, with standard prescription of dialysis, Kt/V will be lower for overweight patients. A confounding issue in this consideration is that V or any measures related to V such as body weight, lean mass, body water, weight-for-height or weight-for-height2 (BMI) in itself influences the survival of patients on dialysis. In other words, while a higher BMI is associated with better survival, a higher BMI through reduced delivered dose of dialysis may lower the survival. That this is not a mere theoretical consideration is suggested by a recent study in which the better survival seen in overweight patients was further improved when adjusted for the reduced dose of dialysis [25]. The second issue is related to patient race and survival on dialysis. While there is a general correlation between higher doses of dialysis and better survival on dialysis, the relationship is, however, not simple [26] and is influenced by race, gender [27], body size [7,28] and possibly other factors. The well-documented better survival of African-American patients on dialysis, despite lower delivered doses of dialysis, defies a ready explanation. The fact that African-American patients in general have larger body mass than comparable groups of Caucasians might be one possible reason for a better survival [4,29,30]. A higher BMI might in turn be an indication of better nutritional status, as biochemical markers of better nutrition co-aggregate with larger body mass [4,13].
Obesity-survival advantage in sick patients without renal failure
Although in general there is a U-curve relationship between BMI and survival in the general population [31], this may not be true for certain subgroups of subjects. For example, a subgroup analysis of a large population study revealed a lack of upturn in the mortality U-curve in obese black subjects [32]. Similarly, a blunted upturn was observed in obese subjects who were sick or smokers [32]. In another large population study that examined the effect of age on the mortalityBMI relationship, the obesity-related mortality risk (RR) did not increase linearly with age because the RR values did not increase among obese patients of certain elderly age groups [32]. Thus, even in non-dialysis subjects, the relationship between overweight and mortality appears not to be uniform. This is further exemplified by the reports in patients with congestive cardiac failure. Obese patients with heart failure had fewer clinical events: with every unit increase in BMI, clinical events decreased by 13% [34]. However, even though obese patients with heart failure might have had fewer clinical events, a recent report from Framingham Heart Study indicates that increased body mass in itself is an independent risk factor for developing heart failure [35]. Thus, obesity is unquestionably associated with higher morbidity and mortality. However, a reasonable supposition, based on the existing data, would be that once ill, excess body weight might confer some survival advantage.
Plausible mechanisms of obesity-associated survival advantage
One proposed mechanism for better survival in obese patients is through the existence of better nutrition. In our study, biochemical markers of better nutrition co-aggregated with higher BMI [4]. However, in the same study, higher BMI retained its positive influence on survival even after adjusting for the parameters of better nutrition, implying that in uraemic patients, higher BMI through mechanisms beyond better nutrition may offset part of the toxic effects of uraemia. Overweight patients have an increase in adipose tissue and are therefore, less likely to suffer from energy deficits. Arguably for this reason, underweight patients on haemodialysis might be more likely to fall ill or tend to recover more slowly from illness than the normal or overweight patients, as shown in the Fleischmann et al. study [4]. Moreover, obese patients in that study had significantly higher serum creatinine, suggestive of greater muscle mass [4]. The presence of greater muscle mass is known to correlate with long-term survival [36] and the presence of larger muscle mass and better nutrition might partly underlie the better survival of obese patients on dialysis. Unlike patients who maintain normal or high-normal body weights, patients who lose body weight often suffer from protein-energy malnutrition and inflammation. The latter is suggested to be cytokine-mediated, and thought to be triggered in response to a variety of dialysis-related stimuli, particularly infection. This state of inflammation in turn is thought to set up a vicious cycle leading to more malnutrition and inflammation [37,38]. Whether obese patients on haemodialysis are less susceptible to widespread systemic inflammation is yet to be determined. An in-depth analysis on the effect of obesity on dialysis-patients' survival, along with detailed consideration for regional differences and mechanisms, has been reviewed recently [39].
Implication for clinical practice
The studies cited supporting an association between overweight and better survival in the dialysis population are mainly observational in nature. It is quite unlikely that an interventional study that induces overweight in dialysis patients will be carried out to test whether a causal relationship exists between obesity and improved survival. In the absence of a clear cause-and-effect study, the linkage between obesity and survival could still be an association. Similarly, any beneficial effect of obesity on dialysis patients could simply be due to other unappreciated factors or medical conditions that could have been favourably modulated by the presence of overweight and improved nutrition. Furthermore, the bulk of the studies supporting an association between obesity and survival are of United States origin and even the DOPPS study is partly United States based. Overweight and obesity is on the steady rise, particularly in the US. In our study, 25% of our patients on haemodialysis were obese (BMI >30) and nearly 40% were overweight (BMI >27.5) [4]. Studies from Southern Europe and Japan did not substantiate a positive association between obesity and survival, most probably due to a reduced prevalence of obesity in these regions.
A prudent practical approach to the management of these patients, while awaiting the results of further research in this area, would be: (i) to monitor serial body weight and BMI, (ii) to be concerned about progressive loss of weight even in overweight patients (and to attempt to delineate the cause, and if possible to treat it effectively), and (iii) to aim to maintain high normal BMI, if necessary with the liberal use of high caloric supplements.
Conflict of interest statement. None declared.
Notes
Correspondence and offprint requests to: Abdulla K. Salahudeen, MD, MSc, FRCP, Professor of Medicine, Department of Medicine, Nephrology Division, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. Email: asalahudeen{at}medicine.umsmed.edu
References