Obesity, Metabolic Health, and the Risk of ESRD
In this prospective study of 21,840 black and white community-living adults, we found that metabolic health modified the association of BMI with risk of incident ESRD, such that higher BMI was associated with lower risk of incident ESRD among those without the metabolic syndrome but not those with the metabolic syndrome. Further, as compared with normal weight individuals without the metabolic syndrome, individuals with the metabolic syndrome had an approximately twofold greater risk of developing ESRD irrespective of weight status, whereas among those without the metabolic syndrome obesity was associated with lower risk of ESRD. These findings suggest that the magnitude and direction of the association of BMI with risk of incident ESRD depends on an individual's concurrent metabolic health. In addition, these results suggest that BMI alone is an inadequate marker of future risk of ESRD.
Our findings provide important context to the results of several prior studies examining the association of BMI with risk of ESRD. Vivante et al. showed that higher BMI was associated with higher risk of developing ESRD in 1.2 million adolescents over a 25-year follow-up period. Other reports including a study of over 3,00,000 subjects by Hsu et al. showed a higher risk of ESRD associated with higher BMI in the general population. These results are consistent with the findings depicted in Figure 1a of the current manuscript in which higher BMI was associated with greater risk of ESRD in the full study sample. Importantly, however, none of the prior studies stratified the analysis by the absence or presence of the metabolic syndrome. This is critical in that higher BMI was associated with lower risk of ESRD in those without the metabolic syndrome, whereas no association of BMI with ESRD risk was observed in those with the metabolic syndrome in the current study. When coupled with our finding that the metabolic syndrome was a powerful risk factor for ESRD, this suggests that the link between higher BMI and greater risk of ESRD reported in prior studies was primarily driven by the association of the metabolic syndrome with ESRD risk and not necessarily by a direct association of BMI with ESRD. If so, it is possible that the magnitude of the association of higher BMI with risk of ESRD was underestimated in these prior studies by combining both individuals with minimal to no metabolic risk factors—who had an inverse association between BMI and ESRD risk in the current study—with individuals with the metabolic syndrome––who were likely driving the association of higher BMI with higher risk of ESRD. Future collaborative studies with larger sample sizes are needed to clarify this issue.
The reasons for our finding of an association of higher BMI with lower risk of ESRD among individuals without the metabolic syndrome are unclear. However, this is in line with several prior studies showing that higher BMI is associated with improved survival in individuals with CKD. The physiological mechanisms underlying this 'obesity paradox' are not well understood. Poor nutritional status or protein-energy wasting are strong predictors of worse outcomes in the CKD population. Recent evidence suggests that protein-energy wasting can be induced by inflammation, an effect that is potentially mediated by suppression of appetite and lowering of albumin due to systemic effects of interleukin-6 or tumor necrosis factor alpha. Protein-energy wasting and increased inflammation are thought to be major underlying mechanisms responsible for increased mortality in this population. Moreover, adipose tissue is now recognized as an active endocrine organ secreting bioactive molecules such as leptin, tumor necrosis factor alpha, and interleukin-6, which are thought to be potential mediators of insulin resistance, diabetes, hyperlipidemia, endothelial dysfunction, and atherosclerosis. It is also possible that in the advanced CKD and ESRD populations, improved nutritional status, elevated adiponectin levels, and increased energy reserves associated with elevated BMI may not only negate but also rise above the deleterious pro-inflammatory and atherogenic effects of increased fat mass, potentially explaining why we observed a protective association of obesity with ESRD risk among individuals who did not meet the criteria for the metabolic syndrome.
The results of our study also support and strengthen the important role the metabolic syndrome has in the development of ESRD. Across all BMI categories, the subgroups with the metabolic syndrome were found to have a twofold higher risk of developing ESRD as compared with normal weight individuals without the metabolic syndrome. This finding is consistent with prior studies showing an association between the presence of the metabolic syndrome and the development and progression of CKD. It is also interesting to note that among all the factors contributing toward the metabolic syndrome, higher blood pressure, higher triglycerides, and higher fasting glucose were the individual metabolic risk factors most strongly associated with increased risk of development of ESRD. Focusing on these factors in clinical practice might prove to be the most efficacious way not only to measure the risk of poor renal outcomes related to higher BMI but also to reduce the risk of ESRD by specifically targeting these factors.
The strengths of our study include a large cohort, using standardized criteria for defining the metabolic syndrome, robust data collection, and utilizing United States Renal Data Service data, which capture more than 95% of the incident ESRD events across the United States. Also, unlike many prior studies that used a composite outcome of all-cause mortality and ESRD, we focused on ESRD as our primary outcome. Our study also had a number of limitations. As with any other observational study, causal relationships cannot be inferred from our observations. Next, we could not establish differential contributions of fat mass or lean mass toward BMI, precluding us from determining the associations of body composition with incident ESRD in this population. It is not clear whether loss of adipose tissue or muscle mass or both lead to worse outcomes in this population. At least one study found that reducing either muscle mass or fat mass was associated with increased mortality. Results from our study may not be applicable to other ethnic groups such as Asians, Hispanics, and other minorities. Also, because of low event numbers in some categories, we may have been underpowered to detect statistically significant associations. Finally, we only had a single measurement of BMI, limiting our ability to establish the impact of weight loss or gain during the follow-up period.
Multiple studies in the past have shown that elevated BMI is associated with increased risk for developing CKD and ESRD. However, none of these studies assessed the effects of metabolic health on this association. Our study shows that a clustering of metabolic risk factors may modify the association of BMI with the risk of incident ESRD, suggesting that BMI alone is a poor marker of future risk of ESRD. Our study highlights the importance of assessing metabolic health status along with BMI and understanding their joint effect on the risk for developing ESRD. Further research to study the effects of elevated BMI among metabolically healthy individuals on incidence of ESRD is needed.
Discussion
In this prospective study of 21,840 black and white community-living adults, we found that metabolic health modified the association of BMI with risk of incident ESRD, such that higher BMI was associated with lower risk of incident ESRD among those without the metabolic syndrome but not those with the metabolic syndrome. Further, as compared with normal weight individuals without the metabolic syndrome, individuals with the metabolic syndrome had an approximately twofold greater risk of developing ESRD irrespective of weight status, whereas among those without the metabolic syndrome obesity was associated with lower risk of ESRD. These findings suggest that the magnitude and direction of the association of BMI with risk of incident ESRD depends on an individual's concurrent metabolic health. In addition, these results suggest that BMI alone is an inadequate marker of future risk of ESRD.
Our findings provide important context to the results of several prior studies examining the association of BMI with risk of ESRD. Vivante et al. showed that higher BMI was associated with higher risk of developing ESRD in 1.2 million adolescents over a 25-year follow-up period. Other reports including a study of over 3,00,000 subjects by Hsu et al. showed a higher risk of ESRD associated with higher BMI in the general population. These results are consistent with the findings depicted in Figure 1a of the current manuscript in which higher BMI was associated with greater risk of ESRD in the full study sample. Importantly, however, none of the prior studies stratified the analysis by the absence or presence of the metabolic syndrome. This is critical in that higher BMI was associated with lower risk of ESRD in those without the metabolic syndrome, whereas no association of BMI with ESRD risk was observed in those with the metabolic syndrome in the current study. When coupled with our finding that the metabolic syndrome was a powerful risk factor for ESRD, this suggests that the link between higher BMI and greater risk of ESRD reported in prior studies was primarily driven by the association of the metabolic syndrome with ESRD risk and not necessarily by a direct association of BMI with ESRD. If so, it is possible that the magnitude of the association of higher BMI with risk of ESRD was underestimated in these prior studies by combining both individuals with minimal to no metabolic risk factors—who had an inverse association between BMI and ESRD risk in the current study—with individuals with the metabolic syndrome––who were likely driving the association of higher BMI with higher risk of ESRD. Future collaborative studies with larger sample sizes are needed to clarify this issue.
The reasons for our finding of an association of higher BMI with lower risk of ESRD among individuals without the metabolic syndrome are unclear. However, this is in line with several prior studies showing that higher BMI is associated with improved survival in individuals with CKD. The physiological mechanisms underlying this 'obesity paradox' are not well understood. Poor nutritional status or protein-energy wasting are strong predictors of worse outcomes in the CKD population. Recent evidence suggests that protein-energy wasting can be induced by inflammation, an effect that is potentially mediated by suppression of appetite and lowering of albumin due to systemic effects of interleukin-6 or tumor necrosis factor alpha. Protein-energy wasting and increased inflammation are thought to be major underlying mechanisms responsible for increased mortality in this population. Moreover, adipose tissue is now recognized as an active endocrine organ secreting bioactive molecules such as leptin, tumor necrosis factor alpha, and interleukin-6, which are thought to be potential mediators of insulin resistance, diabetes, hyperlipidemia, endothelial dysfunction, and atherosclerosis. It is also possible that in the advanced CKD and ESRD populations, improved nutritional status, elevated adiponectin levels, and increased energy reserves associated with elevated BMI may not only negate but also rise above the deleterious pro-inflammatory and atherogenic effects of increased fat mass, potentially explaining why we observed a protective association of obesity with ESRD risk among individuals who did not meet the criteria for the metabolic syndrome.
The results of our study also support and strengthen the important role the metabolic syndrome has in the development of ESRD. Across all BMI categories, the subgroups with the metabolic syndrome were found to have a twofold higher risk of developing ESRD as compared with normal weight individuals without the metabolic syndrome. This finding is consistent with prior studies showing an association between the presence of the metabolic syndrome and the development and progression of CKD. It is also interesting to note that among all the factors contributing toward the metabolic syndrome, higher blood pressure, higher triglycerides, and higher fasting glucose were the individual metabolic risk factors most strongly associated with increased risk of development of ESRD. Focusing on these factors in clinical practice might prove to be the most efficacious way not only to measure the risk of poor renal outcomes related to higher BMI but also to reduce the risk of ESRD by specifically targeting these factors.
The strengths of our study include a large cohort, using standardized criteria for defining the metabolic syndrome, robust data collection, and utilizing United States Renal Data Service data, which capture more than 95% of the incident ESRD events across the United States. Also, unlike many prior studies that used a composite outcome of all-cause mortality and ESRD, we focused on ESRD as our primary outcome. Our study also had a number of limitations. As with any other observational study, causal relationships cannot be inferred from our observations. Next, we could not establish differential contributions of fat mass or lean mass toward BMI, precluding us from determining the associations of body composition with incident ESRD in this population. It is not clear whether loss of adipose tissue or muscle mass or both lead to worse outcomes in this population. At least one study found that reducing either muscle mass or fat mass was associated with increased mortality. Results from our study may not be applicable to other ethnic groups such as Asians, Hispanics, and other minorities. Also, because of low event numbers in some categories, we may have been underpowered to detect statistically significant associations. Finally, we only had a single measurement of BMI, limiting our ability to establish the impact of weight loss or gain during the follow-up period.
Multiple studies in the past have shown that elevated BMI is associated with increased risk for developing CKD and ESRD. However, none of these studies assessed the effects of metabolic health on this association. Our study shows that a clustering of metabolic risk factors may modify the association of BMI with the risk of incident ESRD, suggesting that BMI alone is a poor marker of future risk of ESRD. Our study highlights the importance of assessing metabolic health status along with BMI and understanding their joint effect on the risk for developing ESRD. Further research to study the effects of elevated BMI among metabolically healthy individuals on incidence of ESRD is needed.
Source...