Renal manifestations of the metabolic syndrome

The metabolic syndrome is defined by a constellation of risk factors, including abdominal obesity, impaired glucose tolerance in association with hyperinsulinaemia and insulin resistance, dyslipidaemia characterized by low high-density lipoprotein (HDL)-cholesterol and high triglyceride levels, and hypertension. The World Health Organization (WHO) and the Adult Treatment Panel (ATP) III of the National Cholesterol Education Program have developed clinical criteria for metabolic syndrome (Tables 1 and 2) [1]. Although these organizations have provided somewhat different criteria, the overarching theme from each is aimed at describing the key features. Metabolic syndrome has gained a great deal of attention because it is a precursor to type 2 diabetes and also because it increases cardiovascular disease (CVD) risk, even with levels of glycaemia below that used to define diabetes [1]. The connections between chronic kidney disease (CKD) and CVD are increasingly evident. Indicators of CKD, albuminuria (micro- or macro-) and loss of glomerular filtration rate (GFR) are independently associated with increased CVD risk in the general population, as well as high-risk subgroups [2–7]. These connections are exceedingly complex and include a number of shared traditional risk factors (notably diabetes and hypertension), development of non-traditional risk factors (anaemia, hyperparathyroidism with disordered mineral metabolism, high levels of homocysteine and others) and more severe atherosclerosis. Accordingly, relationships between indicators of CKD and metabolic syndrome have also gained increasing interest. Clinical criteria for metabolic syndrome by ATP III [1] Reproduced with permission from Grundy SM, Brewes HB, Cleeman JI, Smith SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung and Blood Institute/American Heart Association Conference, Circulation 2004; 109: 433–438. Clinical criteria for metabolic syndrome by ATP III [1] Reproduced with permission from Grundy SM, Brewes HB, Cleeman JI, Smith SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung and Blood Institute/American Heart Association Conference, Circulation 2004; 109: 433–438. Clinical criteria for metabolic syndrome by WHO [1] Reproduced with permission from Grundy SM, Brewes HB, Cleeman JI, Smith SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung and Blood Institute/American Heart Association Conference, Circulation 2004; 109: 433–438. Clinical criteria for metabolic syndrome by WHO [1] Reproduced with permission from Grundy SM, Brewes HB, Cleeman JI, Smith SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung and Blood Institute/American Heart Association Conference, Circulation 2004; 109: 433–438. Microalbuminuria is a clinical criterion for metabolic syndrome by the WHO classification [1]. The frequency of microalbuminuria increases across the spectrum from those with normal glucose tolerance (5–10%), to metabolic syndrome (12–20%), to type 2 diabetes (25–40%) [3,8–10]. CVD risk parallels the escalating frequency of microalbuminuria. Endothelial dysfunction is a hallmark of vascular injury associated with atherosclerosis. Loss of albumin in the urine is believed to reflect endothelial dysfunction expressed in the glomerulus that, in turn, reflects the status of the circulation at large. In support of this concept, elevated levels of albuminuria (even within the conventional normal range) are related directly to impaired brachial artery reactivity and to severity of angiographically defined coronary artery disease [11,12]. The aetiologies of endothelial dysfunction and CKD in metabolic syndrome are likely to be multifactorial. Prevalence or probability of microalbuminuria and/or low GFR is progressively amplified by increasing numbers of metabolic syndrome risk factors (Figure 1) [8,13,14]. Such observations have been made in a variety of different groups, including the general population, Native Americans, Australian Aboriginals and treated hypertensives, among others [8,13–16]. Associations were found between various individual risk factors or combinations and indicators of CKD, suggesting that the various components of metabolic syndrome have an important impact. Recent data indicate that fat itself, particularly in the abdomen, is a source of cytokines that produce endothelial damage [17]. In addition, adiponectin, an adipocyte-derived hormone that has antiatherogenic and anti-inflammatory properties, is reduced in those with metabolic syndrome and increased intra-abdominal fat [17]. Prevalence of CKD (estimated GFR <60 ml/min/1.73 m2) (top) and microalbuminuria (urinary albumin-to-creatinine ratio of 30–300 mg/g) (bottom) by number of metabolic syndrome components. Reproduced with permission from Annals of Internal Medicine taken from Chen et al. The metabolic syndrome and chronic kidney disease in US adults. Ann Intern Med 2004; 140: 167–174. Obesity is a defining characteristic of metabolic syndrome, which is increasingly recognized as a cause of CKD. Specific pathological features have been defined and termed ‘obesity-related glomerulopathy’ [18]. The primary features are glomerulomegaly (100% of cases), focal and segmental glomerulosclerosis (80% of cases) and increased mesangial matrix and cellularity (45% of cases) [18–20]. These features bear a striking resemblance to glomerulopathy induced by diabetes and/or hypertension. Similarly, the clinical course of obesity-related glomerulopathy appears to be progressive. After a mean follow-up of 27 months, 14% of patients reached a renal endpoint (doubling of serum creatinine or end-stage renal disease) in the series reported by Kambham et al. [18]. Of particular concern, obesity-related glomerulopathy has been observed in children as young as 3 years of age [20]. The consistent observation of glomerulomegaly underscores the likely importance of glomerular hyperfiltration mechanisms in the pathogenesis of obesity-related glomerulopathy. In the elegant studies of Chagnac et al. [21,22], characteristics of the obese patients, including subdiabetic levels of hyperglycaemia, were consistent with a diagnosis of metabolic syndrome. Their renal physiological studies demonstrated that values for GFR and renal plasma flow (RPF) exceeded those of lean controls by ∼50 and ∼30%, respectively, resulting in increased filtration fraction, an indirect indicator of glomerular hypertension [21]. The renal haemodynamic perturbations may be due, in part, to a higher intake of dietary protein in such individuals who consume an overall excess of nutrients. Interestingly, the studies were performed postprandially (after breakfast), consistent with nutrient-driven effects on GFR and RPF. Renal haemodynamics in obese individuals appear similar to those in early diabetes. In both types 1 and 2 diabetes, we found that an amino acid infusion designed to mimic a protein meal produced an augmented glomerular hyperfiltration response when patients were studied in the fasting state [23,24]. Since the plasma glucose was clamped at an ambient level of ∼200 mg/dl, the changes were not the result of fluctuating degrees of glycaemia. The augmented glomerular hyperfiltration response to the physiological amino acid stimulus was corrected by chronic (3 weeks) strict glycaemic control, but not by acute (36 h) normalization of glucose with insulin infusion or by hormonal blockade with octreotide (glucagon) or indomethacin (prostaglandins) [23–25]. These observations in diabetes have several important implications that may also apply in metabolic syndrome: (i) chronic hyperglycaemia is necessary, but not sufficient, to produce glomerular hyperfiltration; (ii) effects of nutrients (amino acids) on renal haemodynamics can be separated from those of glycaemia; (iii) the data point to dietary protein, acting through an increase in circulating amino acids, as a stimulus for augmented GFR; and (iv) although glucagon and vasodilatory prostaglandins can raise GFR and RPF, they do not appear to be the primary mediators of this renal haemodynamic response to amino acids. Perhaps most importantly, reduction of nutrient intake and weight loss corrects glomerular hyperfiltration in obese individuals. In a study of 17 morbidly obese patients [mean body mass index (BMI): 48 kg/m2] who lost an average of 48 kg at 1 year after bariatric surgery, postprandial GFR and RPF were significantly decreased and approached normal levels, even though the patients were still obese (mean BMI: 32 kg/m2) [22]. Of note, the decrease in GFR was predicted by reduction in glycaemia. Studies in an animal model, the obese Zucker rat, provide further insight into mechanisms of kidney disease in metabolic syndrome. These animals have hyperphagia due to a defect in the brain leptin receptor, which results in obesity and associated hyperglycaemia, hyperinsulinaemia, insulin resistance, dyslipidaemia and hypertension [26,27]. This model exhibits characteristic glomerular hyperfiltration similar to that observed in rat models of overt diabetes [28]. They develop albuminuria and, later, renal failure with histological characteristics of glomerulomegaly, mesangial matrix expansion and hypercellularity, and focal and segmental glomerulosclerosis. In the meticulous studies by Maddox et al. [28], dietary restriction to the same level of intake as lean littermates was highly effective at preventing glomerular injury and reducing mortality in obese Zucker rats. The changes that best predicted renal protection were reduction of GFR due to decreased protein consumption, improved lipids and decreased total calories. Thus, the physiological data are consistent with those obtained in humans and the histological data provide important observations regarding structural correlates. Recently, cultured mesangial cells have been shown to develop a pro-fibrotic and proliferative injury response to increased levels of amino acids designed to resemble a high protein meal [29]. These responses are mediated by increased formation of advanced glycation end-products, presumably the result of greater availability of free amino groups for glycation reactions [30]. Furthermore, formation of advanced glycation end-products by mesangial cells cultured in high glucose is enhanced by the addition of amino acids. The cellular pathway to amino acid-induced fibrosis is signalled through reactive oxygen species, protein kinase C and the mitogen-activated protein kinases/extracellular signal regulated kinases-1,2. Such emerging data regarding cellular mechanisms of injury induced by excess nutrients should lead to novel insights for therapeutic targets. Unhealthy lifestyles, with overeating as a dominant feature, have a number of adverse consequences. Metabolic syndrome has emerged as one of the most important because of its role in damage to vascular target organs, including the kidney. Many unanswered questions remain and should be a research priority, considering the epidemic of obesity in the developed world. The natural history, risk factors and mechanisms of CKD in metabolic syndrome should be elucidated further. Rigorous clinical trials of weight loss and nutritional strategies that include renal endpoints should be a priority. Given what is known about the renal haemodynamic disturbances in persons with diabetes and/or obesity, the safety of ‘high protein–low carbohydrate’ diets, in particular, should be scrutinized carefully. Furthermore, treatment of risk factors (control of hypertension, renin–angiotensin system inhibition, lipid lowering, reduction of glycaemia and insulin resistance) in metabolic syndrome should be evaluated to determine their impact on clinical outcomes. While genetics undoubtedly predispose to metabolic syndrome, the environment is the only aspect that can be controlled at present. Therefore, prevention of obesity and promotion of healthy lifestyles, emphasizing physical activity and prudent eating habits, are likely to be the most effective approaches and should be a public health priority. Conflict of interest statement. None declared.