1 University Renal Research and Education Association, Ann Arbor, MI, USA, 2 Division of Nephrology, University of Michigan and VAMC, Ann Arbor, MI, USA, 3 Klinik fur Nieren-und-Hochdruckkrankheiten, Augusta-Krankenanstalt, Bochum, Germany and 4 Kirin-Amgen, Inc., Thousand Oaks, CA, USA
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Abstract |
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Methods. The prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) provided baseline demographic, comorbidity and BMI data on 9714 HD patients in the US and Europe (France, Germany, Italy, Spain, and the UK) from 19962000. Using multivariate survival analyses, we evaluated BMImortality relationships in HD subpopulations defined by continent, race (black and white), gender, tertiles of severity of illness (based on a score derived from comorbid conditions and serum albumin concentration), age (<45, 4564, 65), smoking, and diabetic status.
Results. Relative mortality risk decreased with increasing BMI. This was statistically significant (P<0.007) except for the smallest subgroup of patients who were <45 years old and were also in the healthiest tertile of comorbidity. All else equal, BMI <20 was consistently associated with the highest relative mortality risk. Overall a lower relative mortality risk (RR) as compared with BMI 2324.9, was found for overweight (BMI 2529.9; RR 0.84, P=0.008), for mild obesity (BMI 3034.9; RR 0.73, P=0.0003), and for moderate obesity (BMI 3539.9; RR 0.76, P=0.02).
Conclusion. In a wide variety of HD patient subgroups, differing with respect to their baseline health status, increasing body size correlates with a decreased mortality risk. This contrasts with the association between BMI and mortality in the general population, and deserves further study.
Keywords: body mass index; haemodialysis; mortality
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Introduction |
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In the US general population, overweight (BMI 2530) and obesity (BMI 30) appear as risk factors for cardiovascular, cancer, and all-cause mortality [6]. However, the relative increase in mortality risk associated with overweight and obesity (vs normal BMI 2324.9 kg/m2) is larger in healthier individuals without, as compared with sicker individuals with, a history of chronic disease and/or smoking [6]. Conversely, being lean (lower BMI) predicts much smaller increases in mortality risk in healthier subjects with no history of chronic disease or smoking [6]. Thus, it is hypothesized that as the overall health of a population decreases, high BMI may become weaker, and low BMI stronger as a predictor of increased mortality risk, all else equal.
This hypothesis can be extrapolated to HD-treated patients (Figure 1). As a group they have a very high burden of chronic illness, perhaps accounting for the failure of most prior studies to identify a mortality risk associated with high BMI. One subgroup of HD-treated patients, namely Asian Americans, does have a significant increase in mortality risk for high BMI [5]. As a subgroup of US HD patients, Asian Americans are on average healthier, as evidenced by a lower prevalence of comorbidities and an approximately 35% lower mortality risk, than white Americans [5]. Therefore, overall health status may also influence BMImortality relationships between HD patients. The prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) [7] allows comparison of BMImortality relationships in the US and Europe and among a variety of healthier, as compared with sicker HD patient subgroups, such as younger patients, never-smokers and those with less chronic illnesses (comorbidities).
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Subjects and methods |
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The study was initiated sequentially in the US, then Europe, and finally Japan, between 1996 and 1999. The sample analysed included black and white patients in the US (n=5982) and Europe (n=3732) with baseline data for BMI. Because of the small number of events in Japan-DOPPS to date, and because of prior observations of different BMImortality relationships in Asian American dialysis patients, these groups were excluded. A small number of patients known to be HIV positive or those with a diagnosis of AIDS (n=81) were excluded from the analysis to avoid the possibility that this group might unduly influence mortality risk estimates for lower BMI patients.
Analyses
BMI was measured as an individual's dry weight at study entry (kg), divided by the square of height in meters. There were over 8806 patient-years of follow-up from the US, plus 4214 patient-years from Europe. A total of 2580 deaths (2026 in the US and 554 in Europe) were observed in this sample (data collected through September 2000). Univariate statistics were computed for all of the predictor variables used in the survival analyses both for the overall study population and for specific HD patient subgroups. PROC GLM or Logistic regression (SAS 8.0) was used to compare baseline measurements of continuous variables and comorbidity prevalence between patient groups.
Survival was analysed as time from patient entry into the study to patient death, using multivariate Cox proportional hazards regression [8]. Patients were censored from contributing additional survival data to the analyses following a switch in treatment modality to peritoneal dialysis (n=274) or transplantation (n=683) or following change to a non-DOPPS HD facility (loss to follow-up) (n=1757), or at the time of the last round of data collection for a given facility, whichever came first. To account for differences in the duration of treated ESRD at study entry, all survival models were left-truncated [9]. All analyses were adjusted for independent country-effects (by stratification), and for age, gender, race, and smoking status. Models were also adjusted for serum albumin and for each of the comorbidity indicators listed in Table 1 (unless otherwise stated).
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Subsequently the data were combined to facilitate analysis of BMImortality relationships in a number of healthier and sicker patient subgroups. The relationship between mortality and BMI was examined both between, and within, a sickest, a healthiest, and a middle tertile severity of illness group. Patients were categorized into these groups using a comorbidity score derived from a Cox analysis of the entire study population, which determined regression coefficients that corresponded to independent mortality risks associated with serum albumin and with each comorbidity variable listed in Table 1. By summing the coefficients that corresponded to each individual's serum albumin concentration and comorbidity profile a continuous numeric score of severity of illness was generated at the patient-level.
A variety of additional analyses were also performed. BMImortality relationships were determined separately for age groups (age <45; age 4560; age >60); smokers (defined as any current or former history of smoking) and non-smokers; diabetics and non diabetics; patients with or without documented vascular disease; and for patients who were both <45 years old and in the healthiest comorbidity tertile. The higher range of BMI was modelled in categories corresponding with mild obesity, BMI 3034.9 kg/m2 (n=1055); moderate obesity, BMI 3539.9 kg/m2 (n=355); and severe obesity, BMI 40 kg/m2 (n=153). Analyses were performed with and without adjustment for vascular diseases, diabetes, dialysis dose, dialysis treatment time, pre-dialysis serum creatinine, and nPCR to investigate whether these adjustments might alter the conclusions of the study. All analyses used the SAS Statistical Software System version 8.0. Statistical significance is reported at a P-value of 0.05.
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Results |
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From the lowest to the highest BMI groups, mean pre-dialysis creatinine concentration increased, nPCR decreased and mean albumin concentration was relatively unchanged (Table 2). Delivered dialysis dose decreased with increasing BMI, despite a significant trend towards longer dialysis treatment times for patients with higher BMI. The crude mortality rate decreased from 26.9 deaths per 100 patient-years in the BMI <20 group, to 14.1 deaths per 100 patient-years for the BMI
30 group (Table 2
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Multivariate analyses
Simultaneously adjusting for all of the factors shown in Table 1, the mortality risk decreased as BMI increased in both the US and Europe samples (Figure 2
). A significant inverse linear correlation of relative mortality risk (RR) with ln(BMI) was found in both samples (P<0.0001). In both the US and Europe, overall mortality risk was significantly lower for BMI
30 as compared with the reference BMI group 2324.9 (US RR 0.77, P=0.002; Europe RR 0.61, P=0.01). The patterns are not significantly different for the US and Europe.
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Table 3 shows BMImortality relative mortality risk estimates derived from modelling BMI as a categorical variable for a variety of HD patient subpopulations. Within all patient subgroups, the highest adjusted mortality risk was found for BMI <20, as compared with BMI 2324.9 (significant at P<0.05, except for the two groups with the smallest numbers of patients and events). Within all patient subgroups (Table 2
), the lowest adjusted mortality risk was found for BMI
30. Comparisons within 10 of the 13 subgroups found that the mortality risk ratio for BMI
30 was significantly less than the risk ratio for BMI 2324.9 (P<0.05). In blacks, whites, non-smokers, non-diabetics, and patients in the middle tertile group for severity of illness, the mortality risk ratio for the obese group (BMI
30) was significantly less than the risk ratio for the overweight group (BMI 2529.9, P<0.05). Similar trends in relative mortality risk with increasing BMI, albeit not statistically significant, were found for the two subgroups with the smallest numbers of patients and patient deaths (patients <45 years old at study entry and patients from this age group who were also in the lowest severity of illness score tertile).
To further investigate the relationship between high BMI and mortality, the upper range of BMI for the entire DOPPS sample was modelled in categories corresponding with overweight, mild, moderate, and severe obesity. As compared with a normal BMI reference group (BMI 2324.9) significantly lower adjusted mortality risks were found for overweight (RR 0.84, P=0.008), mild obesity (RR 0.73, P=0.0003), and moderate obesity (RR 0.76, P=0.02). In comparing the 153 patients with BMI in the severe obesity range to this reference group, a relative mortality risk of 0.83 was found (P=0.331). As compared with an overweight reference group (BMI 2529.9), mild obesity (BMI 3034.9) was associated with a decrease in mortality risk that was borderline significant (P=0.08). No other comparisons of mortality risk within the overweight, mild, moderate, and severe obesity categories produced statistically significant differences.
Analyses performed without adjustments for vascular diseases and diabetes did not alter the results of the study. Neither adjustment for dose of dialysis and duration of dialysis, or for pre-dialysis serum creatinine and nPCR, were found to significantly alter the association between BMI and mortality.
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Discussion |
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In the US, irrespective of the measurement (BMI, per cent ideal body weight, or weight-for-height percentiles), several investigators have found a significant inverse relationship between mortality risk and body size in HD populations [25,14]. Less has been published relating BMI to mortality for HD patients in Europe. A decrease in mortality risk with increasing BMI was reported for a population of mostly young, non-diabetic patients treated with maintenance HD in France during the 1970s [15]. The present study extends prior observations by finding that higher BMI is associated with improved survival in a representative sample drawn from contemporary HD patients in the US and five European countries.
We were also interested in a new hypothesis, namely, whether overweight might be associated with an increased mortality risk within healthier, as compared with sicker HD patient populations. Observations both in the general population and in a subpopulation of ESRD patients in the US suggested the possibility of such effect modification by health status/severity of illness burden [5,6]. To investigate this hypothesis BMImortality relationships were defined for a variety of patient subgroups. In one approach we used the data on patient-level comorbidity, serum albumin concentration and survival to describe three equal-sized severity-of-illness groups (tertiles). Patients received a score based on their individual comorbidity profile and serum albumin concentration (methods). This approach worked well to divide the total study population into strata, which were characterized by a gradient of increasing comorbidity prevalence and worsening survival as one moved from the healthiest to the sickest group (Tables 1 and 3
). Contrary to the hypothesis, a survival benefit was found for overweight patients (BMI 2529.9), which was improved upon in the obese patient category (BMI
30) across the healthier, as well as the sicker, groups of HD-treated patients. Even within a cohort of <45 year old patients with low comorbidity overweight/obesity was not associated with decreased survival.
Increasing dialysis dose correlates with improved survival in high and low BMI patients. However, delivered dialysis dose tends on average to be lower in large people. In contrast, dialysis treatment times are found to be longer in large people. Recently, the critical importance of adjusting for confounding effects of body size when describing the effects of dialysis dose on mortality has been highlighted [16,17]. For the primary analyses presented in this paper we deliberately choose not to adjust for dialysis dose. This approach was taken because lower dialysis dose is a plausible mechanism through which increasing BMI might be harmful for HD patients [18]. However, dose was adjusted for in sensitivity analyses and this did not significantly alter the results. Similarly, the primary analysis did not adjust for dialysis treatment time. It might be hypothesized that increased prescription of longer treatment times could favour improved survival for larger patients. However, adjustments for treatment time with or without dose adjustment did not change the direction or magnitude of the BMI associations with mortality. Similarly, the shape of the BMImortality associations was also unaffected by whether or not adjustments were made for vascular comorbidities and diabetes.
The present study included a large number of patients and a large number of events. Nonetheless, the average follow-up time per patient is relatively short, 1.34±0.95 years. It might be argued that insufficient time had accrued for individuals to suffer adverse consequences of their higher body size in this study. Yet in a previous population-based study in HD patients higher BMI, in prevalent or incident HD patients, was shown to confer a survival advantage even as late as 5 years after the date of measurement [2]. Furthermore, cross-sectional studies in the US and Europe have found that body size is significantly lower the longer patients have been on dialysis prior to the time of survey sampling [13,19]. Thus, for the average prevalent patient receiving HD treatment and entering a study, higher body size is not likely to have developed just prior to study start while receiving HD treatment. Instead higher BMI most likely predates by a significant length of time the study start date, and for many may have been present close to or even well before the time of diagnosis of ESRD. Both this assumption and a particular statistical technique, which was used for survival analysis in this paper, namely left-truncation [9], address some of the concerns regarding duration of follow-up. A left-truncated survival analysis allows patients to inform survival for the period of their ESRD life history that is followed in the study. This is dependent on their duration of ESRD at study start date. The mean duration of ESRD at study start was 2.9±4.5 years (95% of the population fall between 0 and 12.5 years of ESRD). With left-truncation, a survival analysis is produced that covers the duration of ESRD life history provided for by the patients in this study. In a left-truncated model an average of 1 year of follow-up for 100 patients, with different duration of ESRD, can be as informative as 10 years of follow-up per patient for 10 patients.
Large numbers of patients meet the WHO guidelines for overweight (BMI 2530, n=2541) and mild (grade I) obesity (BMI 3035, n=1054). A smaller number met definitions for moderate (BMI 3540, n=355) and severe (BMI >40, n=153) obesity. The major analyses grouped all patients with BMI >30 kg/m2 together. In an additional analysis using the entire study population, we subdivided obese patients into the above three grades of obesity. The severe obesity group had a slightly higher mortality than the mild to moderate obesity group but the difference was small and far from statistically significant. Although the relative mortality risk appears to level off for BMI subgroups beyond mild obesity, either an advantage or a disadvantage in terms of survival for individuals at the margins of the data (extremes of body size) could be missed because of a lack of power. However, a precise estimate of mortality risk is provided for BMI groups corresponding to overweight and grade I obesity, for whom in the general population, but not apparently the ESRD population, adverse health events are substantially increased, all else equal [6].
The explanations for the marked differences in mortality risk patterns by BMI ranges within the HD population vs the general population are not known. Although higher BMI correlates with increased body fat mass, and hence increased energy reserve, it is not a perfect correlate. For instance, BMI cannot differentiate a weight change that is due to an increase in muscle-mass from that due to an increase in fat-mass or that due to increased water weight. In this study, the shape of the BMI mortality relationship was unchanged in a sensitivity analysis, which simultaneously adjusted for other measures that might separately characterize fat-free mass. These measures included height (a surrogate for stature), pre-dialysis creatinine (a surrogate for muscle mass), plus/minus regression derived estimates of body water. Therefore, at least some of the benefits of higher BMI in HD patients may accrue from improved nutritional status. Perhaps patients with increased nutritional reserves on HD are better able to withstand the cumulative stresses over time of insufficient protein-calorie intakes, inflammation, chronic acidosis, infections, vascular access failures, hospitalizations and suboptimal small- and middle-molecule solute clearances.
Survival effects in higher BMI individuals may outweigh the harmful effects of being overweight or obese on cardiovascular disease. Perhaps other causes of accelerated atherosclerosis, characteristic of the uraemic milieu, drive vascular disease in all HD patients, rendering the traditional independent risk factor overweight/obesity relatively less important [20]. Alternately, suboptimal nutrient intake may combine with other processes such as inflammation to promote accelerated vascular disease and malnutrition [20]. Lastly, it is also important to recognize that patient selection may play a role in the observed results. Although the analyses adjust for the presence of a wide range of comorbidities, data characterizing severity of disease (for example, severity of cardiovascular disease) are limited. If a non-random distribution of disease severity were to exist across BMI groups, this could impact the shape of the association between BMI and mortality.
The strengths of this paper are founded in the design of the DOPPS study. Attention to representative sampling within countries, and the ongoing prospective subject enrolment starting in 1996, makes the results relevant to current HD populations across the US and five European countries. Detailed data collection allowed adjustment for demographics and comorbidities and multiple approaches to testing the hypothesis. The large sample size and large number of observed events provided power to characterize important relationships with precision. The magnitude of the differences in survival across BMI groups (Table 2) emphasizes the clinical significance of the results. The statistical methodologies employed multivariate survival analyses with multiple adjustments for confounding and for duration of ESRD. Finally, multiple supplemental analyses of the effects of comorbidity adjustments, dialysis dose adjustments, and BMI cutpoints were also performed to enhance the validity of the study.
This study defines the consistency of the association of mortality with BMI in HD populations. It cannot, however, provide causal inference. Although increasing body size correlates significantly with a decreased mortality risk for patients with ESRD on HD, it will require further study to determine if an intervention, which promotes higher BMI, or prevents a reduction in weight (and thus BMI), can improve survival. Potentially modifiable exposures including smoking, vascular access type, dialyser and reuse practices, anaemia, dietary protein intake and delivered dialysis dose have been shown to correlate with serum albumin concentrations [21]. Initially, there is a need to identify those factors that are independently associated with BMI and or changes in BMI in dialysis patients. If these identified factors are amenable to intervention then the present study supports testing hypotheses that such interventions could improve survival in HD patients.
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Acknowledgments |
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Notes |
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References |
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