2 associated with an increase in cardiovascular mortality [13, 14]. Ninomiya et al. recently examined the relationship between Mets and CKD [15]. They performed a slope analysis of the association between the glomerular ﬁltration rate (GFR) slope and Mets by using a multiple regression model. GFR decreased signiﬁcantly faster in patients with 4 or more Mets components compared with those who had 1 or no components. Moreover the mean of the GFR slope was signiﬁcantly lower in subjects with 3 Mets components in the 60 year and over group. In a large cohort of the NHANES III study with baseline normal renal function, Chen et al. examined the risk of developing CVD following patients for more than 20 years [16]. Interestingly, there also was a 2-fold increase in the risk of microalbuminuria that correlates with the number of components of Mets. Moreover, even low-grade albuminuria below the conventional cut-oﬀ point for albuminuria was associated with increased prevalence of CKD [17]. Data from the MESA [18] and LIFE studies [19] clearly demonstrated that albuminuria is one of the strongest risk factors for cardiovascular disease (CVD). 3. Adipose Tissue As an Active Endocrine Organ There are multiple changes in adipose tissue in obesity inc- luding increase in numbers and size of adipocytes, inﬁltra- tion of adipose by mononuclear cells, rarefaction of blood vessels, increases in adipocyte turnover rate, diﬀerentiation, and apoptosis [20]. The capillary diﬀusion capacity is reduced in patients with obesity and, in contrast with the response of lean subject, the adipose blood ﬂow does not increase in response to food in obese patients [21]. Since the discovery of leptin as an adipocyte-derived satiety factor, adi- pose tissue is increasingly being considered as an endocrine organ. Adipose tissue secretes into the circulation a number of proteins and nonprotein factors that regulate glucose and lipid metabolism throughout the body. Among these bioac- tive adipokines, only adiponectin (ADN), leptin, adipsin, and visfatin are almost synthesized exclusively by adipocytes. In obese patients, the production of ADN is reduced [22– 24]. ADN is a 30 kDa protein present as oligomers in the blood stream and has insulin-sensitizing, antiatherogenicity, and anti-inﬂammatory properties. Reduction of ADN levels is a consistent feature among obese patients who have evidence of IR and often develop diabetes mellitus. ADN plasma levels also negatively correlate with coronary artery disease and dyslipidemia in both mice and humans [25–28]. Overexpression or AND administration reduces oxidative stress, inﬂammation, IR, and vascular damage. Becker et al. found that low ADN levels in mild to moderate kidney disease were correlated with cardiovascular events [29]. The potential link between ADN levels and low-grade albuminuria was ﬁrst observed in a clinical study where essential hypertensive patients had a negative correlation between ADN levels and low-grade albuminuria [30]. Later on, similar results were also obtained in obese patients from diﬀerent ethnic groups [31, 32]. Despite some controversial observations [33, 34], clinical data strongly suggest the Cardiology Research and Practice potential causative role of ADN in the development of albuminuria in obese patients. An important contribution in understanding the potential link between obesity and kidney damage comes from the work by Sharma [32]. In a recent study, he showed that ADN knockout mice had baseline increased albuminuria (twice normal values) with podocyte foot process eﬀacement. Morphologically, the endothelium appeared to be normal under electron microscopy. Podocytes expressed the AdipoR1 receptor and ADN regulated an isoform of NAPDH oxidase through the AMPK pathway [32]. When treating ADN knockout mice with ADN, pro- teinuria was reversed and foot processes were normalized. In mice, Sharma et al. [32] also demonstrated that ADN deﬁciency was a susceptibility factor for early diabetic kidney disease. Consequently, the podocyte may play an important role in determining albuminuria associated with obesity [35]. The role of endothelial dysfunction may be important for albuminuria as well. At the present time, no data are available to document the presence of glomerular endothelial dysfunction in the presence of microalbuminuria. On the other hand, it has been established that podocyte dysfunction contributes to endothelial dysfunction [36, 37]. The increase of visceral fat promotes synthesis of proin- ﬂammatory adipokines which cause tissue-speciﬁc increase in reactive oxygen species derived from NADPH oxidase. Adipose tissue oxidative stress results in the development of systemic oxidative stress and inﬂammation, which further lead to the development of metabolic abnormalities. Leptin, a 167 amino acid polypeptide, is expressed mainly by adipocytes; leptin concentration positively correlates with adiposity [38], and hyperleptinemia is an independent risk factor for coronary artery disease [39] and a strong predictor of acute myocardial infarction [40]. Additionally, leptin has been implicated in many atherogenic processes, including platelet aggregation and thrombosis [41–43]; production of inﬂammatory cytokines, for example, TNF-α, IL-6, and IL- 12 [44]; calciﬁcation of vascular smooth muscle cells [45]. Interestingly, recent reports have demonstrated that leptin possesses cytokine-like properties and that elevated plasma leptin levels occur concomitantly with elevated IL-6 and C- reactive protein in human obesity, the Mets, and noninsulin- dependent diabetes mellitus [46–48]. Animal testing showed that leptin induces proliferation of glomerular endothelial cells, enhances glomerular TGF-β1 beta expression, and increases collagen type IV mRNA production [49]. These factors result in focal glomerulosclerosis, glomerular and mesangial glucose uptake, and proteinuria [49]. Additionally, leptin is also associated with adrenergic activation, increased blood pressure and tachicardia, contributing to obesity- related hypertension and kidney damage [50–53]. In recent years, a great deal of attention has been focused on the orexigenic peptide ghrelin which is predominantly secreted by the stomach [54, 55]. Patients with obesity- related Mets have reduced ghrelin circulating levels. Ghrelin has important vascular actions; it acutely stimulates produc- tion of NO in vascular endothelium through a PI3-kinase- dependent mechanism involving phosphorylation of Akt which directly phosphorylates and activates eNOS leading to increased production of NO [56]. This signaling pathway