The metabolic syndrome, also known as the cardiometabolic syndrome (CMS), is a constellation of metabolic, cardiovascular, and renal abnormalities that include insulin resistance with compensatory hyperinsulinemia, central or visceral obesity, hypertension (HTN), dyslipidemia, micro‐albuminuria (MAU), fibrinolytic and inflammatory abnormalities, endothelial dysfunction, oxidative stress, and hypercoagulability. 1 , 2 , 3 Collectively, these components convey a substantial risk of cardiovascular disease and chronic kidney disease (CKD). 2 , 3 , 4 The development of MAU is now widely accepted as a marker of systemic endothelial dysfunction and, importantly, is increasingly recognized as an integral component of the CMS. 1 , 2 , 3 There are varying diagnostic criteria for the CMS. 1 , 2 , 3 The World Health Organization (WHO) criteria for diagnosis of the CMS includes the presence of MAU and recognizes the importance the CMS conveys with respect to both cardiovascular and renal end points. 1
IS THERE A LINK AMONG OBESITY, INSULIN RESISTANCE/HYPERINSULINEMIA, AND CKD?
The relationship between obesity and insulin resistance, with compensatory hyperinsulinemia, is considered essential in the development of the CMS. There is mounting epidemiologic evidence indicating an important role in their contribution to the development and progression of CKD. Data from the National Health and Nutrition Examination Survey (NHANES), in addition to results from the Okinawa Dialysis Study Registry, reveal a parallel increase in the prevalence of obesity and end‐stage renal disease (ESRD) indicating that obesity is an important contributor to renal disease. 3 , 5 The difficulty in interpreting these data are the substantial contributions of type 2 diabetes mellitus (T2DM) and HTN to the development and progression of CKD. To account for the presence of T2DM and HTN, a review of over 320,000 individuals from Kaiser Permanente and the US Renal Data System (USRDS) registry adjusted for both, and similarly revealed an increasing risk of ESRD with increasing body mass index (BMI) in kg/m2. 6
Evaluating the association with CKD rather than ESRD as BMI increased, an analysis of 11,104 participants in the Physicians' Health Study 7 demonstrated that individuals in the highest quintile (>26.6 kg/m2) of BMI had an odds ratio (OR) of 1.45 for development of CKD when compared with the lowest BMI quintile (<22.7 kg/m2). Results from the Framingham Offspring Study 8 also demonstrated that as BMI increased, the risk of new‐onset CKD increased (OR, 1.23). 8 Studies have demonstrated that BMI is independently associated with MAU. In the Prevention of Renal and Vascular End‐Stage Disease (PREVEND) study, 9 the prevalence of MAU in men increased from 9.5% with a BMI <25 kg/m2 to 29.3% with a BMI >30 kg/m2.
In addition to the relationship between obesity and CKD, insulin resistance has also been correlated with CKD in numerous population studies. Recent evidence supports a correlation between the development of insulin resistance and decline in renal function. 10 In this study, the glucose disposal rate was significantly less in participants with CKD (6.91±2.46 mg/kg/min) than that of healthy subjects (9.93±1.33 mg/kg/min), which correlates to reduced insulin sensitivity in patients with CKD. This study also reported a positive correlation between glucose disposal rate and creatinine clearance, and a negative correlation between glucose disposal rate and serum creatinine level. Furthermore, in a case‐control study of Japanese individuals, patients with T2DM and CKD (serum creatinine level >2.0 mg/dL) demonstrated more than two times lower insulin sensitivity than a group of normoalbuminuric subjects. 11 In addition to these studies, an analysis of 6453 nondiabetic NHANES III participants demonstrated that as serum insulin, serum C‐peptide, percentage glycosylated hemoglobin, and insulin resistance increased, the OR for CKD increased. 12
Beyond evaluating associations of insulin resistance and obesity with CKD, it is paramount to assess the contribution of MAU to this link. In a study of more than 6000 participants, each component of the CMS was noted to be associated with an increased prevalence of CKD and MAU. 13 A study of 2415 patients with type 1 diabetes mellitus in the Finnish Diabetic Nephropathy (FinnDiane) study 14 also demonstrated that insulin resistance was positively correlated with increasing MAU and creatinine clearance. The prevalence of the CMS was 28% in subjects with normoalbuminuria, 44% in subjects with MAU, 62% in macroalbuminuric subjects, and 68% in patients with ESRD. In addition, individuals with the CMS had an OR for developing diabetic kidney disease of 3.75. Another study involving a cohort including 10,096 nondiabetic subjects with normal baseline kidney function in the Atherosclerosis Risk in Communities (ARIC) study 15 demonstrated that patients with the CMS have an OR for developing CKD of 1.43. Furthermore, during 9 years of follow‐up, participants with the CMS at baseline had a greater risk of developing CKD (OR, 1.24) after adjustment for the subsequent development of T2DM and HTN. 15
Insulin resistance has been linked to MAU independently of other components of the CMS. 16 A subanalysis of 982 nondiabetic individuals in the Insulin Resistance in Atherosclerosis Study (IRAS) 17 revealed a decreasing prevalence of MAU in the presence of increasing insulin sensitivity (OR, 0.86), when adjusted for age and sex. In another evaluation of the Framingham Offspring Study, 18 more than 2000 insulin‐resistant participants categorized as having zero, one, two, or all three of the following: impaired glucose tolerance, HTN, and/or the central metabolic syndrome (two or more traits of obesity, dyslipidemia, or hyperinsulinemia) had a greater proportion of MAU. Furthermore, groups with hyperinsulinemia tended to have a greater proportion of subjects with MAU than those without hyperinsulinemia. A review of 5659 NHANES III 19 men and women showed a strong positive correlation between MAU and high fasting blood sugars. MAU was more common in women (OR, 2.2) and in men (OR, 4.1) with the CMS as compared with those without it.
A GLIMPSE AT A NEW PARADIGM
The CMS is a state of metabolic dysregulation composed of a cluster of abnormalities including insulin resistance accompanied by hyperinsulinemia and central, or visceral, obesity. In concert, visceral obesity and insulin resistance/hyperinsulinemia convey a state of fibrinolytic and inflammatory abnormalities, endothelial dysfunction, oxidative stress, and hypercoagulability that lead to an increased risk of CKD. This manifests clinically as MAU, which is now accepted as a marker of systemic endothelial dysfunction. The importance of MAU in the CMS is increasingly being recognized and is included in the WHO definition of the CMS. The current evidence is promising. Few of the studies to date, however, have attempted to adjust for the presence of HTN and T2DM in elucidating a role for the CMS in the development and progression of CKD.
Acknowledgments and disclosure: We wish to thank Allison Farris for her assistance in preparing this manuscript. Our research is supported by grants from the National Institutes of Health (R01‐HL‐63904‐01), the Veterans Affairs Merit System (0018), and AstraZeneca.
References
- 1. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus: provisional report of a WHO consultation. Diabet Med. 1998;15:539–553. [DOI] [PubMed] [Google Scholar]
- 2. Govindarajan G, Whaley‐Connell A, Muga M, et al. The metabolic syndrome as a cardiovascular risk factor. Am J Med Sci. 2005;330:311–318. [DOI] [PubMed] [Google Scholar]
- 3. Sarafidis PA, Whaley‐Connell A, Sowers JR, et al. Cardiometabolic syndrome and chronic kidney disease: what is the link? J Cardiometab Syndr. 2006;1:58–65. [DOI] [PubMed] [Google Scholar]
- 4. Garg JP, Bakris GL. Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease. Vasc Med. 2002;7:35–43. [DOI] [PubMed] [Google Scholar]
- 5. Iseki K, Ikemiya Y, Kinjo K, et al. Body mass index and the risk of development of end‐stage renal disease in screened cohort. Kidney Int. 2004;65:1870–1876. [DOI] [PubMed] [Google Scholar]
- 6. Hsu CY, McCulloch CE, Iribarren C, et al. Body mass index and risk for end‐stage renal disease. Ann Intern Med. 2006;144:21–28. [DOI] [PubMed] [Google Scholar]
- 7. Gelber RP, Kurth T, Kausz AT, et al. Association between body mass index and CKD in apparently healthy men. Am J Kidney Dis. 2005;46:871–880. [DOI] [PubMed] [Google Scholar]
- 8. Fox CS, Larson MG, Leip EP, et al. Predictors of new‐onset kidney disease in a community‐based population. JAMA. 2004;291:844–850. [DOI] [PubMed] [Google Scholar]
- 9. de Jong PE, Verhave JC, Pinto‐Sietsma SJ, et al., for the PREVEND Study Group . Obesity and target organ damage: the kidney. Int J Obes Relat Metab Disord. 2002;26(suppl 4):S21–S24. [DOI] [PubMed] [Google Scholar]
- 10. Kobayashi S, Maesato K, Moriya H, et al. Insulin resistance in patients with chronic kidney disease. Am J Kidney Dis. 2005;45:275–280. [DOI] [PubMed] [Google Scholar]
- 11. Emoto M, Nishizawa Y, Maekawa K, et al. Insulin resistance in non‐obese, non‐insulin‐dependent diabetic patients with diabetic nephropathy. Metabolism. 1997;46:1013–1018. [DOI] [PubMed] [Google Scholar]
- 12. Chen J, Muntner P, Hamm LL, et al. Insulin resistance and risk of chronic kidney disease in nondiabetic US adults. J Am Soc Nephrol. 2003;14:469–477. [DOI] [PubMed] [Google Scholar]
- 13. Chen J, Muntner P, Hamm LL, et al. The metabolic syndrome and chronic kidney disease in U.S adults. Ann Intern Med. 2004;140:167–174. [DOI] [PubMed] [Google Scholar]
- 14. Thorn LM, Forsblom C, Fagerudd J, et al. Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study). Diabetes Care. 2005;28:2019–2024. [DOI] [PubMed] [Google Scholar]
- 15. Kurella M, Lo JC, Chertow GM. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J Am Soc Nephrol. 2005;16:2134–2140. [DOI] [PubMed] [Google Scholar]
- 16. Hoehner CM, Greenlund KJ, Rith‐Najarian S, et al. Association of the insulin resistance syndrome and microalbuminuria among nondiabetic native Americans. The Inter‐Tribal Heart Project. J Am Soc Nephrol. 2002;13:1626–1634. [DOI] [PubMed] [Google Scholar]
- 17. Mykkanen L, Zaccaro DJ, Wagenknecht LE, et al. Microalbuminuria is associated with insulin resistance in nondiabetic subjects: the Insulin Resistance Atherosclerosis Study. Diabetes. 1998;47:793–800. [DOI] [PubMed] [Google Scholar]
- 18. Meigs JB, Jacques PF, Selhub J, et al. Fasting plasma homocysteine levels in the insulin resistance syndrome: the Framingham Offspring Study. Diabetes Care. 2001;24:1403–1410. [DOI] [PubMed] [Google Scholar]
- 19. Palaniappan L, Carnethon M, Fortmann SP. Association between microalbuminuria and the metabolic syndrome: NHANES III. Am J Hypertens. 2003;16:952–958. [DOI] [PubMed] [Google Scholar]