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Metabolic Syndrome and the Risk for Chronic Kidney Disease among Nondiabetic Adults
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J Am Soc Nephrol 16: 2134-2140, 2005
Manjula Kurella*, Joan C. Lo{dagger}, and Glenn M. Chertow*
Divisions of * Nephrology and {dagger} Endocrinology, Departments of Medicine and {ddagger} Biostatistics and Epidemiology, University of California San Francisco, San Francisco; and Division of Research, Kaiser Permanente of Northern California, Oakland, California
"The metabolic syndrome is independently associated with an increased risk for incident CKD in nondiabetic adults. After adjusting for the subsequent development of diabetes and hypertension during the 9 yr of follow-up, the OR of incident CKD among participants with the metabolic syndrome was 1.24.....The risk was independent of potential confounding factors such as age, gender, race, education, BMI, alcohol and tobacco use, coronary heart disease, and physical activity. There were graded relations among the number of clinical traits of the metabolic syndrome, HOMA-insulin resistance, and fasting insulin levels and the risk for CKD, suggesting a pathophysiologic basis for these findings. Moreover, the increased risk for CKD was evident even after adjusting for hypertension (a potential cause and consequence of kidney disease) and incident diabetes, another known mediator of CKD. In sum, these findings suggest that the metabolic syndrome directly contributes to the development of CKD.....this study identifies a large, previously not well-recognized segment of the population for whom CKD risk reduction efforts may be beneficial......use of statins may slow CKD progression....Several lines of evidence suggest that dyslipidemia may be an important factor in the development and progression of CKD. Observational data and a recent meta-analysis suggest that elevated triglycerides and low HDL are independent risk factors for the development or acceleration of CKD and that the use of statins may slow CKD progression(30-34). Others have speculated a direct role for insulin resistance and hyperinsulinemia (35), inflammation resulting from lipotoxicity (36,37), reduced nephron number, and increased excretory load (38,39)."
Abstract
The metabolic syndrome is a risk factor for the development of diabetes and cardiovascular disease; however, no prospective studies have examined the metabolic syndrome as a risk factor for chronic kidney disease (CKD). A total of 10,096 nondiabetic participants who were in the Atherosclerosis Risk in Communities study and had normal baseline kidney function composed the study cohort. The metabolic syndrome was defined according to recent guidelines from the National Cholesterol Education Program. Incident CKD was defined as an estimated GFR (eGFR) <60 ml/min per 1.73 m2 at study year 9 among those with an eGFR ≥60 ml/min per 1.73 m2 at baseline. After 9 yr of follow-up, 691 (7%) participants developed CKD. The multivariable adjusted odds ratio (OR) of developing CKD in participants with the metabolic syndrome was 1.43 (95% confidence interval [CI], 1.18 to 1.73). Compared with participants with no traits of the metabolic syndrome, those with one, two, three, four, or five traits of the metabolic syndrome had OR of CKD of 1.13 (95% CI, 0.89 to 1.45), 1.53 (95% CI, 1.18 to 1.98), 1.75 (95% CI, 1.32 to 2.33), 1.84 (95% CI, 1.27 to 2.67), and 2.45 (95% CI, 1.32 to 4.54), respectively. After adjusting for the subsequent development of diabetes and hypertension during the 9 yr of follow-up, the OR of incident CKD among participants with the metabolic syndrome was 1.24 (95% CI, 1.01 to 1.51). The metabolic syndrome is independently associated with an increased risk for incident CKD in nondiabetic adults.
To explore whether the risk for CKD in individuals with the metabolic syndrome was mediated by the subsequent development of diabetes or hypertension, we fit additional models adjusting for incident diabetes and hypertension at follow-up (note: individuals with baseline diabetes were excluded from the analysis). Over 9 yr of follow-up, 10% of the cohort developed incident diabetes and 19% developed hypertension. After inclusion of incident diabetes and hypertension, the association between the metabolic syndrome and incident CKD remained statistically significant (RR, 1.24; 95% CI, 1.01 to 1.51). We also compared baseline and follow-up BP measurements stratified by the presence of hypertension to explore whether the difference in CKD incidence might be explained by differences in BP over time. Among those without baseline hypertension, baseline mean systolic BP (116 versus 112 mmHg) and mean diastolic BP (71 versus 69 mmHg) were significantly higher in individuals with the metabolic syndrome (P < 0.0001 for both comparisons). After 9 yr of follow-up, mean systolic BP (125 versus 122 mmHg) was significantly higher in individuals with the metabolic syndrome (P < 0.001), although mean diastolic BP (69 versus 70 mmHg) was not (P = 0.47). Among those with baseline hypertension, baseline and follow-up BP measurements did not differ by the presence or absence of the metabolic syndrome.
Introduction
The metabolic syndrome, also known as the insulin resistance syndrome, is characterized by abdominal obesity, dyslipidemia, hypertension, and hyperglycemia and is present in approximately 20% of US adults (1). Individuals with the metabolic syndrome are at increased risk for diabetes and cardiovascular disease (2), as well as cardiovascular and all-cause mortality (3,4). The prevalence of chronic kidney disease (CKD) is also rising, affecting approximately 8 million adults in the United States (5). Cross-sectional studies have demonstrated a link between the metabolic syndrome and CKD (6,7). However, whether the metabolic syndrome contributes to the development of CKD is unknown.
Diabetes is a major risk factor for the initiation and progression of CKD (8,9), and individuals with evidence of the metabolic syndrome have a substantial risk for developing type 2 diabetes over time (2). Epidemiologic studies have linked the metabolic syndrome with an increased risk for microalbuminuria, an early marker of kidney injury (7,10-13); few studies have evaluated the relation between the metabolic syndrome and CKD (6,7). These studies have been limited by cross-sectional design, the inclusion of subjects with diabetes, and the use of proxies of insulin resistance, rather than recently proposed clinical criteria defining the metabolic syndrome (14). To date, no prospective longitudinal studies have examined the risk for CKD among individuals with the metabolic syndrome. It remains unclear whether the syndrome is a cause or a consequence of reduced kidney function and whether the associations are independent of diabetes.
To determine whether the metabolic syndrome was associated with the development of CKD, we examined data from a large, community-based, prospective cohort of adults. We hypothesized that among individuals with normal or near-normal kidney function at baseline, the metabolic syndrome would be associated with the development of CKD over time. Moreover, we hypothesized that this association would be independent of diabetes and hypertension, the leading causes of CKD in the United States.
Discussion
Although individual components of the metabolic syndrome have been implicated in the development or progression of CKD, few studies have examined the joint effect of these commonly observed clinical traits. Several cross-sectional studies have noted an association between the metabolic syndrome, defined by recent guidelines, or proxy measures of insulin resistance and microalbuminuria in individuals with and without diabetes (7,10-13). Two studies previously examined the association between the metabolic syndrome and CKD, both using data from the Third National Health and Nutrition Examination Survey (NHANES III). In a cross-sectional analysis of nondiabetic adults in NHANES III, Chen et al. (6) demonstrated correlations among insulin resistance, hyperinsulinemia, and the prevalence of CKD. These authors also reported a 2.6-fold increased prevalence of CKD among adults in NHANES III with the metabolic syndrome using the clinical definition used here (7).
Using data from participants in the ARIC Study, a large, prospective, community-based cohort, we demonstrated that the metabolic syndrome, absent diabetes, is associated with an increased risk for incident CKD, defined as progression to eGFR <60 ml/min per 1.73 m2 over a 9-yr period. The risk was independent of potential confounding factors such as age, gender, race, education, BMI, alcohol and tobacco use, coronary heart disease, and physical activity. There were graded relations among the number of clinical traits of the metabolic syndrome, HOMA-insulin resistance, and fasting insulin levels and the risk for CKD, suggesting a pathophysiologic basis for these findings. Moreover, the increased risk for CKD was evident even after adjusting for hypertension (a potential cause and consequence of kidney disease) and incident diabetes, another known mediator of CKD. In sum, these findings suggest that the metabolic syndrome directly contributes to the development of CKD.
The difference in risk reported in our study and a previous cross-sectional study (7) may reflect several factors, including confounding by the inclusion of individuals with diabetes and the degree to which reduced kidney function may be a cause of insulin resistance. Nevertheless, because the metabolic syndrome is present in a considerable fraction of the nondiabetic adult population (22), this study identifies a large, previously not well-recognized segment of the population for whom CKD risk reduction efforts may be beneficial.
The mechanisms of hypertensive and diabetic injury leading to CKD have been well described (23-25). In this study, the association between the metabolic syndrome and CKD in nondiabetic individuals remained robust even after accounting for the subsequent development of diabetes and hypertension, suggesting that the risk for CKD is not solely attributable to these conditions. Obesity is implicated in the development focal segmental glomerulosclerosis and glomerulomegaly (26,27) and has also been associated with an increased risk for ESRD in some but not all studies (28,29). Several lines of evidence suggest that dyslipidemia may be an important factor in the development and progression of CKD. Observational data and a recent meta-analysis suggest that elevated triglycerides and low HDL are independent risk factors for the development or acceleration of CKD and that the use of statins may slow CKD progression (30-34). Others have speculated a direct role for insulin resistance and hyperinsulinemia (35), inflammation resulting from lipotoxicity (36,37), reduced nephron number, and increased excretory load (38,39).
This study has several strengths, including the large, community-based biracial sample, long duration of follow-up, exclusion of individuals with diabetes, adjustment for a number of potential confounding factors, and the use of a clinically meaningful end point (eGFR < 60 ml/min per 1.73 m2) rather than a surrogate marker of kidney injury. Nevertheless, several limitations may affect the interpretation of these results. We excluded individuals without follow-up serum creatinine measurements. Because these individuals were older and more likely to have the metabolic syndrome, exclusion of these individuals would be expected to bias the study results toward the null. We did not have measurements of urinary protein excretion; thus, some of the individuals who were included in the analytic cohort may have had incipient kidney disease with normal kidney function. Early effects of the metabolic syndrome may include an increase rather than decrease in GFR, owing to the effects of insulin and IGF-1, which promote glomerular hyperfiltration (40,41). To the degree that proteinuria leads to CKD independent of the metabolic syndrome, the results presented here may have overestimated the risks associated with the metabolic syndrome. However, as with hypertension (or more so), proteinuria is more likely a consequence rather than a cause of CKD. We used eGFR rather than directly measured GFR to define CKD. Differential misclassification of individuals with borderline CKD also may have resulted in biased estimates. However, when we used gender-specific serum creatinine cutoffs rather than eGFR to define CKD, the results were unchanged, suggesting that the findings presented here are robust. The current definition of the metabolic syndrome gives equal weight to each trait, an assumption that may not necessarily be valid, because each trait may not contribute equally to the risk for CKD (as suggested in Table 5). Although we accounted for differences in the prevalence of hypertension at baseline and follow-up and conducted secondary analyses in which individuals with baseline and incident hypertension were excluded, we cannot rule out the possibility that subtle differences in BP over time may have contributed to CKD risk. Finally, our findings do not rule out the possibility that the metabolic syndrome is a marker and not a causative factor in the development of CKD. Interventional studies that target the components of the metabolic syndrome are needed to clarify these putative mechanisms of kidney injury.
In summary, we found that nondiabetic adults with the metabolic syndrome had an increased risk for developing CKD over 9 yr of follow-up, independent of baseline confounding factors and the subsequent development of diabetes and hypertension. Future studies should address whether weight reduction, exercise, and other measures to increase insulin sensitivity, as well as interventions that directly target biochemical components of the metabolic syndrome, may reduce the risk for CKD in these individuals.
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