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The Metabolic Syndrome as a Risk Factor for Chronic Kidney Disease: More than a Fat Chance?

Jeffrey R. Schelling and John R. Sedor

Departments of Medicine and Physiology and Biophysics, School of Medicine, Case Western Reserve University, and Kidney Disease Research Center, Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, Ohio

Correspondence to Dr. John R. Sedor, Rammelkamp Center, R415, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109-1998. Phone: 216-778-4993; Fax: 216-778-8248; E-mail: john.sedor{at}case.edu

The metabolic syndrome, also known as syndrome X or insulin resistance syndrome, is characterized by abdominal obesity, hyperglycemia, hypertension, hypertriglyceridemia, and reduced HDL cholesterol. In this issue of the Journal of the American Society of Nephrology, Wisse (1) describes the link between chronic inflammation of visceral adipose and the insulin resistance and pathologic features that characterize the metabolic syndrome. The prevalence of the metabolic syndrome in the United States is 47 million and rising (2), as a result of the current obesity and diabetes epidemics. Journal of the American Society of Nephrology readers are well aware that chronic kidney disease (CKD) is also increasingly common, with an estimated 8 million people in the United States with GFR <60 ml/min (Third National Health and Nutrition Examination Survey). Many aspects of the metabolic syndrome phenotype are associated with CKD, suggesting that individuals with visceral obesity are at increased risk for progressive loss of renal function.

Several groups have examined the relationship between the metabolic syndrome and CKD. Hoehner et al. (3) correlated the metabolic syndrome profile and microalbuminuria in a cross-sectional study of American Indians from Wisconsin and Minnesota. After stratification, individuals with three or more metabolic syndrome traits had a 2.3-fold increased odds of having microalbuminuria compared with a control group without the syndrome. Palaniappan et al. (4) and Chen et al. (5) extracted data from the Third National Health and Nutrition Examination Survey database, which contains detailed clinical information from >6000 subjects. Both studies found a statistical association between metabolic syndrome and microalbuminuria. Chen et al. also discovered a significant correlation between number of metabolic syndrome factors and GFR <60 ml/min. Individual traits that confer greatest risk were hypertension and hyperglycemia (5), which is not surprising, because both factors predispose to CKD pathogenesis and/or progression (6,7).

We conclude from these reports that the metabolic syndrome is related to renal dysfunction, but a cause-and-effect relationship cannot be clearly established from these studies. Because of considerable overlap between clinical features of the metabolic syndrome and diabetes, CKD risk in individuals with the metabolic syndrome may reflect the presence of known risk factors for CKD initiation and progression—hypertension and diabetes—rather than an independent effect. One approach to identifying a distinction would be to compare the prevalence of CKD in metabolic syndrome cohorts who do or do not satisfy diagnostic criteria for diabetes. Until such a study is conducted, it is reasonable to view the renal risks and consequences of the metabolic syndrome and diabetes as indistinguishable.

Some data do suggest that the metabolic syndrome may independently cause CKD. In addition to identifying BP and hyperglycemia as risks for CKD in the metabolic syndrome, Chen et al. (5) observed that increased waist circumference significantly correlated with microalbuminuria and GFR decline, suggesting that obesity may be an independent risk for CKD. An association between obesity and the nephrotic syndrome was first recognized years ago (8). More recently, Iseki et al. (9) showed a statistical association between body mass index and incidence of ESRD in Japanese men, even after adjusting for comorbid risks, such as BP and proteinuria. A large renal pathology study demonstrated that obesity-related glomerulopathy, which is characterized by focal segmental glomerulosclerosis and glomerulomegaly, increased in incidence from 0.2 to 2% of all biopsy diagnoses during the 15-yr period of the study (10). None of the patients demonstrated a histologic pattern consistent with diabetic nephropathy, the presumed pathology associated with the metabolic syndrome. These studies raise the possibility that obesity, which is a cardinal feature of the metabolic syndrome, may lead to CKD. However, as mentioned earlier, this may be difficult to prove, in this case because obesity is also a risk for hypertension and diabetes (11).

Obesity and insulin resistance are prominent features of the metabolic syndrome, and both have been associated with secretion of inflammatory mediators and activation of inflammation-associated signaling pathways (12–15). The role of specific mediators in the pathogenesis of the metabolic syndrome, including leptin, IL-6, TNF-, adiponectin, and acylation-stimulating protein, are discussed in detail in the review by Wisse (1) in this issue. Until recently, adipocytes were viewed as the most likely source of soluble, metabolic syndrome mediators, a notion that is corroborated by in vitro studies demonstrating adipocyte capacity to secrete proinflammatory cytokines (16). However, two groups have published studies within the past year implicating macrophages, which infiltrate fat tissue, as the principal site of obesity-related cytokine synthesis (17,18). Because many of these cytokines have been suggested to mediate renal disease pathophysiology (19), it is tempting to speculate that progressive kidney disease could also be regulated by proinflammatory cytokines in the context of the metabolic syndrome. Other potential mechanisms include physical compression of kidney parenchyma by adipose tissue, reduced birth weight and nephron number, enhanced glucocorticoid activity, or altered uric acid metabolism (20–22). We are hopeful that large National Institutes of Health–sponsored diabetic nephropathy initiatives, such as FIND (23) or the mouse consortium (www.niddk.nih.gov/fund/diabetesspecialfunds/consortia/AMDCC.pdf) will identify candidate molecules, which will elucidate novel pathogenetic pathways that may help to define unique mechanisms of renal injury associated with diabetes and the metabolic syndrome.

In the small subset of patients with metabolic syndrome and absence of glucose intolerance, we advocate close monitoring for subsequent development of diabetes, because these patients are at extremely high risk for diabetes and diabetes-related complications. In metabolic syndrome patients with hypertension and hyperglycemia, it is clear that aggressive BP and glucose control is warranted, for the prevention of renal as well as extrarenal disease manifestations of hypertension and diabetes. One cannot be as certain whether treatment of other components of the metabolic syndrome will necessarily have an impact on CKD progression. However, recent studies indicate that susceptibility to CKD increases with the number of metabolic syndrome traits (5), and other reports have linked obesity and dyslipidemia to CKD (24), thereby supporting the idea that aggressive obesity- and lipid-lowering therapies have the potential to ameliorate renal disease progression in the setting of the metabolic syndrome. More intensive investigation into the specific role of obesity and hyperlipidemia in CKD progression is warranted, particularly because the prevalence of diabetes, obesity, and ESRD continue to climb at alarming rates.

	Acknowledgments

 
The authors were supported by NIH grants DK064719, DK057329, and DK059997.

	References

Top References

 

1. Wisse BE: The inflammatory syndrome: The role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 15: 2792–2800, 2004[Abstract/Free Full Text]
2. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 41: 1–12, 2003[Medline]
3. Hoehner CM, Greenlund KJ, Rith-Najarian S, Casper ML, McClellan WM: Association of the insulin resistance syndrome and microalbuminuria among nondiabetic native Americans. The Inter-Tribal Heart Project. J Am Soc Nephrol 13: 1626–1634, 2002[Abstract/Free Full Text]
4. Palaniappan L, Carnethon M, Fortmann SP: Association between microalbuminuria and the metabolic syndrome: NHANES III. Am J Hypertens 16: 952–958, 2003[CrossRef][Medline]
5. Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J: The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 140: 167–174, 2004[Abstract/Free Full Text]
6. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329: 977–986, 1993[Abstract/Free Full Text]
7. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 330: 877–884, 1994[Abstract/Free Full Text]
8. Weisinger JR, Kempson RL, Eldridge FL, Swenson RS: The nephrotic syndrome: A complication of massive obesity. Ann Intern Med 81: 440–447, 1974
9. Iseki K, Ikemiya Y, Kinjo K, Inoue T, Iseki C, Takishita S: Body mass index and the risk of development of end-stage renal disease in a screened cohort. Kidney Int 65: 1870–1876, 2004[CrossRef][Medline]
10. Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD: Obesity-related glomerulopathy: An emerging epidemic. Kidney Int 59: 1498–1509, 2001[CrossRef][Medline]
11. Rosenbaum M, Leibel RL, Hirsch J: Obesity. N Engl J Med 337: 396–407, 1997[Free Full Text]
12. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS: A central role for JNK in obesity and insulin resistance. Nature 420: 333–336, 2002[CrossRef][Medline]
13. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE: Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikk. Science 293: 1673–1677, 2001[Abstract/Free Full Text]
14. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS: Protection from obesity-induced insulin resistance in mice lacking TNF- function. Nature 389: 610–614, 1997[CrossRef][Medline]
15. Perreault M, Marette A: Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med 7: 1138–1143, 2001[CrossRef][Medline]
16. Rajala MW, Scherer PE: Minireview: The adipocyte—At the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144: 3765–3773, 2003[Abstract/Free Full Text]
17. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796–1808, 2003[CrossRef][Medline]
18. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112: 1821–1830, 2003[CrossRef][Medline]
19. Wolf G, Chen S, Han DC, Ziyadeh FN: Leptin and renal disease. Am J Kidney Dis 39: 1–11, 2002[CrossRef][Medline]
20. Hales CN, Ozanne SE: For debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure. Diabetologia 46: 1013–1019, 2003[CrossRef][Medline]
21. Hall JE, Brands MW, Henegar JR: Mechanisms of hypertension and kidney disease in obesity. Ann N Y Acad Sci 892: 91–107, 1999[CrossRef][Medline]
22. Masuzaki H, Yamamoto H, Kenyon CJ, Elmquist JK, Morton NM, Paterson JM, Shinyama H, Sharp MG, Fleming S, Mullins JJ, Seckl JR, Flier JS: Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. J Clin Invest 112: 83–90, 2003[CrossRef][Medline]
23. Zager PG, Knowler WC, Freedman BI, Elston RC, Family Investigation ND: Genetic determinants of diabetic nephropathy: The Family Investigation of Nephropathy and Diabetes (FIND). J Am Soc Nephrol 14: S202–S204, 2003[Abstract/Free Full Text]
24. Fried LF, Orchard TJ, Kasiske BL, Lipids and Renal Disease Progression Meta-Analysis Study Group: Effect of lipid reduction on the progression of renal disease: A meta-analysis. Kidney Int 59: 260–269, 2001[CrossRef][Medline]

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