Obesity-Initiated Metabolic Syndrome and the Kidney: A Recipe for Chronic Kidney Disease?

Abstract

Metabolic syndrome, originally described in 1988 as “syndrome X” by Reaven et al. (1), has evolved in our collective thinking from a vague association of common chronic disease states to a formally defined cluster of clinical traits with adverse impact on cardiovascular risk (2). The cause is incompletely understood but represents a complex interaction among genetic, environmental, and metabolic factors, clearly including diet (3,4) and level of physical activity (4,5). These abnormalities are mediated by—and interconnected by—complex pathways that affect energy homeostasis at cellular, organ, and whole-body levels. This review focuses on obesity-initiated metabolic syndrome, first to provide a pathogenetic overview of extrarenal metabolic derangements; second to consider predisposing conditions shaped by genetic or environmental factors, including growth constraints in utero; and finally to consider the impact of metabolic syndrome on the kidney in its prediabetic phase. The pathogenesis of hypertension in the context of metabolic syndrome is considered separately in this series. Similarly, central nervous system pathways that contribute to disordered energy homeostasis is addressed in detail by others. The mechanisms of irreversible renal injury from hypertension and overt diabetes are well documented and are beyond the scope of this review; nonetheless, they loom large in the long-term renal future of the patient with metabolic syndrome. The current worldwide epidemic of obesity-initiated metabolic syndrome, with its potential for renal damage, mandates our commitment to early renal protection in the obese and to vigorous prevention of obesity in both pediatric and adult populations. Metabolic Syndrome Defined: A Work in Progress The Adult Treatment Panel III (ATPIII) of the National Cholesterol Education Program (NCEP) (2) defines metabolic syndrome clinically as any three of the following five traits (Table 1): abdominal obesity, impaired fasting glucose (reflecting insulin resistance), hypertension, hypertriglyceridemia, and low HDL cholesterol. In addition, the NCEP ATPIII recognizes prothrombotic and proinflammatory states as characteristic of metabolic syndrome (2). Importantly, as subsequent paragraphs detail, these simple clinical criteria for diagnosis belie the emerging complexity of the underlying metabolic derangements (6). Thus, insulin resistance is viewed as the essential common denominator of metabolic syndrome, regardless of cause. Abdominal obesity, now identified solely by waist circumference criteria (Table 1), is the single most common cause of insulin resistance, and key mechanisms that mediate this pathway are becoming clear (6). Hypertension [defined in this high-risk context as ≥130/85 (2)] and the typical pattern of atherogenic dyslipidemia—hypertriglyceridemia, low HDL cholesterol, and increase in small dense LDL particles (2)—are also likely downstream consequences of insulin resistance with identifiable contributions from specific organs. Clinical criteria also do not emphasize the role of disordered skeletal muscle metabolism in this syndrome or highlight for the clinician the therapeutic power of regular exercise to offset insulin resistance. Finally, concepts now evolving from research advances suggest that the current clinical definition identifies individuals at a relatively advanced stage, well beyond onset of irreversible organ/tissue injury. Consequently, one immediate research challenge is to define, in the temporal evolution of metabolic syndrome, where interventions can both reverse metabolic derangements and prevent the tissue damage that conveys long-term risk. Table 1: Clinical criteria for diagnosis of metabolic syndromePrevalence and Cardiovascular Risks of Metabolic Syndrome On the basis of the Third National Health and Nutrition Examination Survey (NHANES III; 1988 to 1994), the prevalence of metabolic syndrome in the U.S. population ≥20 yr of age is 23.7% (7), rising to >40% in those ≥60 yr of age and in those from specific geographic regions (e.g., south Texas) (8). This compares with a 30.5% prevalence of obesity (body mass index [BMI] ≥30) and a 64.5% prevalence of overweight (BMI ≥25) in the NHANES III U.S. population sample, reflecting marked increases of 7 to 10%, respectively, in the previous decade (9). Among non-U.S. populations, prevalence ranges from 49.4% of 1625 hypertensive individuals in Spain (10), 19.8% in Greece (11), and 17.8% in older Italians (12). The last cohort exhibited a stepwise increase in insulin resistance severity (by Homeostasis Model Assessment) with increasing numbers of metabolic syndrome features (12). Importantly, overt metabolic syndrome is not limited to adults (13). Cruz et al. (14) examined 126 overweight Hispanic children who were aged 8 to 13 and had a family history of type 2 diabetes; 62% exhibited abdominal obesity, and 30% met criteria for metabolic syndrome. As in adults, obesity in the pediatric population is