1. Top of page
  2. Abstract
  3. Pathophysiology
  4. Epidemiology
  5. Conclusions
  6. References

The term metabolic syndrome or cardiometabolic syndrome describes the clustering of several cardiovascular and renal risk factors, including type 2 diabetes mellitus, central obesity, hypertension, and dyslipidemia. Over the past 15 years, several studies have examined the association between the metabolic/cardiometabolic syndrome or its central component, insulin resistance, with the presence of elevated urine albumin excretion. Intrarenal changes associated with the cardiometabolic syndrome result in elevated glomerular filtration rate, impaired pressure natriuresis, endothelial dysfunction related to changes in nitric oxide and, hence, impaired renal autoregulation and enhanced chronic inflammation. The aforementioned changes that occur in the cardiometabolic syndrome all contribute to the development of renal injury. While this review focuses on the epidemiology and mechanisms associated with vascular/renal injury, it must be remembered that prevention and treatment of kidney disease require a multifactorial approach. Weight loss through diet and exercise can reverse many of these pathophysiologic adaptations. Pharmacologic intervention should be aimed at achieving guideline goals and include insulin sensitizers to aid in tight glycemic control, lipid control, blockade of the renin-angiotensin-aldosterone system for blood pressure reduction, and anti-inflammatory therapies.

For over a century, investigators have observed the coexistence of type 2 diabetes mellitus (DM), hypertension, dyslipidemia, and obesity.1 Today this is known as the “metabolic syndrome,” or “cardiometabolic syndrome (CMS),” originally identified in 1988 as “syndrome X” by Gerald M. Reaven.2 At the beginning of the 21st century, varying definitions for the syndrome emerged. The first, from the World Health Organization (WHO), proposed that criteria for the syndrome include the presence of insulin resistance (IR), identified by the presence of DM, impaired glucose tolerance, or for those with normal fasting glucose, by a glucose uptake below the lowest quartile of the values of the background population.3 Moreover, the diagnosis of the syndrome required the presence of at least two additional components, including hypertension, elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, obesity, and microalbuminuria (MAU), which is a recent addition to the cluster. The second definition was included in the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) recommendations, which proposed that the clinical identification of the syndrome would require three of the following five criteria: abdominal obesity, elevated triglycerides, low HDL cholesterol, blood pressure (BP) ≥130/85 mm Hg, and fasting glucose ≥110 mg/dL (6.1 mmol/L).4 Apart from the obvious absence of IR from this second definition, the main difference between these was the presence of MAU in the WHO definition.

MAU is defined as urine albumin excretion (UAE) between 30 and 300 mg/d if measured by 24-hour urine collection, or 30–300 mg/g if measured with the use of spot albumin:creatinine ratio (ACR). The presence of MAU is an early sign of increased vascular permeability and a clinical manifestation of abnormal vascular responsiveness.5 In recent studies, both in the general population and in high-risk individuals, the presence of MAU is associated with significant increases in the risk of cardiovascular disease (CVD) events.5 The progression of UAE to levels exceeding the limits for MAU is considered a sign of overt nephropathy and is associated with faster deterioration of kidney function.6 The low predictive value of MAU for chronic kidney disease (CKD) was not known during the 1990s and, thus, most of the studies in the field of the CMS and nephropathy focused on MAU as a factor reflecting the progression of kidney function rather than as a marker of vascular dysfunction.

This review will summarize the epidemiologic data on the association between the CMS and IR with CKD, to give a perspective on the progress of our knowledge in this field. We will also describe background experimental evidence that suggests possible pathways linking IR, compensatory hyperinsulinemia, and related parameters with renal injury, independent of components of the CMS that are established (hypertension, DM) or emerging (obesity, dyslipidemia) risk factors for CKD.


  1. Top of page
  2. Abstract
  3. Pathophysiology
  4. Epidemiology
  5. Conclusions
  6. References

Possible Pathways Linking IR and Hyperinsulinemia With CKD. Within the concept of the CMS, various aspects related to IR could potentially have deleterious effects on kidney function (Figure 1), apart from parameters that are already well known risk factors (e.g., hypertension, DM)7 for CKD. Moreover, IR and subsequent hyper-insulinemia appear to be an important link connecting the obesity epidemic with CKD8; numerous proinflammatory cytokines and hormones originating from adipose tissue, such as tumor necrosis factor-α, interleukin-6, leptin, and resistin are integral to the development of IR.9 In the natural history of the syndrome, resistance to insulin-stimulated glucose uptake would result in an increase in insulin levels to maintain glycemic control. This hyperinsulinemic state, which can precede the development of DM by many years, can have deleterious effects on end-organs such as the kidney and can lead to the development of several features of the syndrome.10 Recent experimental data suggest that the earliest evidence of structural change, glomerular hypertrophy, appears within the period of hyperinsulinemia and before the onset of DM.11 Several studies have examined the effects of compensatory hyperinsulinemia on the kidney. Most of them, however, focused on tubular function, where insulin has been repeatedly shown to have an important antinatriuretic effect that is preserved in insulin-resistant states.12,13 However, only a few studies have examined the effect of insulin on glomerular function.


Figure 1. Possible mechanisms linking insulin resistance and compensatory hyperinsulinemia with chronic kidney disease. [UPWARDS ARROW] increased; IGF-1=insulin-like growth factor-1; RAS=renin-angiotensin system; ATI=angiotensin type 1; TGF-β=transforming growth factor-β; ET-1=endothelin-1; [DOWNWARDS ARROW] =decreased

Glomerular Permeability. In regard to the impact of insulin on glomerular permeability to albumin and other proteins, most previous studies did not provide reliable data, as they were performed in small numbers of subjects, in an uncontrolled fashion, or with the use of insulin boluses.12 One study, however, simultaneously examined the acute effects of high or low insulin infusion during euglycemic, hyperinsulinemic conditions on systemic and renal vascular protein permeability in 12 normoalbuminuric type 2 diabetic patients and 12 healthy volunteers.14 Hyperinsulinemia was found to significantly increase UAE and clearance rates in patients by about 50%, but not in control subjects. These results suggest that insulin directly and selectively increases the urinary excretion of albumin in patients with DM without affecting systemic albumin permeability.

Salt Sensitivity. The physiologic Na+-retaining action of insulin has led to the hypothesis that IR and hyperinsulinemia contribute to the development of salt sensitivity in hypertensive patients.15 In various studies, IR has been associated with salt sensitivity independently of the presence of obesity.16 On the other hand, diabetic patients with increased UAE have been shown to have greater salt sensitivity than patients with .17 In another recent study, investigators examined the associations of sensitivity of BP to salt intake, IR, and albuminuria.18 Subjects with normoalbuminuria showed no changes in switching from a low- to high-Na+ diet, but in microalbuminuric patients this switch resulted in increases in B P, UAE, renal plasma flow, and intraglomerular pressure. Since microalbuminuric patients also had significantly lower insulin sensitivity and intraglomerular pressure was positively related to UAE and inversely correlated with insulin sensitivity, the authors concluded that the contribution of IR to greater salt sensitivity in hypertension could be one mechanism leading to increased glomerular pressure and UAE.

Glomerular Filtration Rate. Evidence supports a direct effect of insulin on glomerular filtration rate (GFR). In experimental animals, insulin produced a slight increase in GFR,19 possibly due to a direct vasodilatory effect. It is not known, however, what effect chronic hyperinsulinemia would have on GFR in insulin-resistant states, in which insulin-mediated vasodilatation is severely impaired and insulin-mediated sympathetic stimulation is unaffected, so that an imbalance in favor of systemic vasoconstriction occurs.13,20 The associated renal vasoconstriction may be associated with a shift toward a reduction in renal plasma flow and GFR. However, it is plausible that reduced Na+ excretion capacity and renal plasma flow associated with hyperinsulinemia would lead to reduced Na+ delivery to sites proximal to the macula densa, which, in turn, would induce afferent vasodilation and glomerular hyperfiltration. Future studies are needed to elucidate these maladaptive mechanisms.

Cell Proliferation. Studies have shown that important maladaptive events in the progression of diabetic nephropathy are early mesangial cell proliferation, increased growth factor expression, and extracellular matrix expansion.21 Although insulin has long been known to increase proliferation of vascular cells, the discovery of insulin-like growth factors (IGF) has added a great deal to our understanding of insulin mitogenic actions. IGF-1 is a very important growth hormone produced by vascular smooth muscle cells under a variety of stimuli, among which is insulin.22 Elevated insulin levels, such as those present in insulin-resistant states, can promote vascular cell proliferation through action on the IGF-1 receptor.10 Human glomerular mesangial cells both secrete IGF-1 and possess IGF-1 receptors.23 Further, physiologic concentrations of IGF-1 and pharmacologic concentrations of insulin can induce mesangial cell growth.24,25 Moreover, in vitro studies have shown that insulin markedly increases the rate of protein synthesis from mesangial cells and can alter the type of interstitial and basement membrane collagens they excrete. In particular, elevated insulin concentrations cause mesangial cells to synthesize predominantly collagens type I and III, and not collagen type IV, only the latter of which resembles normal extracellular matrix composition. Mesangial cells cultured in the presence of insulin failed to synthesize the normal collagen pattern after withdrawal of insulin. This suggests insulin can evoke a mesangial phenotypic change.25

Apart from a direct proliferative effect and its impact on IGF-1, insulin may interfere with the progression of kidney disease through its effect on other growth factors, such as transforming growth factor-β (TGF-β). In vitro studies have previously shown that insulin significantly increases TGF-β1 production not only from mesangial cells,26 but also from proximal renal tubular cells—and thus contributes to extracellular matrix production.27 Moreover, TGF-β1 and IGF-1 were found to increase the expression and activity, respectively, of another profibrotic cytokine, connective tissue growth factor, which also enhances fibrosis, a process important in the pathogenesis of diabetic nephropathy.28

Renin-Angiotensin-Aldosterone System (RAAS). In parallel to the above, there is mounting evidence that insulin resistance/hyperinsulinemia contributes to abnormalities in the systemic and intrarenal RAAS. In vivo, hyperinsulinemia significantly increases both the aldosterone and pressor responses to angiotensin II (Ang II).29 Previous data suggest that insulin is necessary for Ang II-induced contraction of mesangial cells in vitro, providing a possible link between insulin and Ang II-mediated renal injury.30 Ang II alone has a slight effect on TGF-β1 and collagen protein production from cultured mesangial cells, but this effect is multiplied by the addition of insulin.26

Endothelial Dysfunction. Insulin has previously been shown to stimulate endothelin-1 (ET-1) production from endothelial cells in vitro31 and to raise plasma ET-1 levels in vivo in both healthy and insulin-resistant persons.32 Epidemiologic studies have also shown increased plasma ET-1 and significant associations with markers of IR in insulin-resistant states.33 Previous case-control studies reported an increase in ET-1 levels in patients with DM or hypertension and MAU,34 suggesting an involvement of ET-1 in the development of nephropathy in these patients. In experimental studies, apart from being a potent vasoconstrictor of the renal vasculature, ET-1 has been shown to have mitogenic effects on mesangial cells.35 Among others, ET-1 stimulates protein kinase C-regulated phospholipase D, which hydrolyzes phospholipid substrates and induces the generation of phosphatidic acids that stimulate proliferation in mesangial cells.35 Taking into account the growing evidence of the involvement of endothelin peptides in various tissue functions, an important effect on the progression of kidney disease should not be excluded.

In healthy subjects, insulin promotes endothelium-dependent vasodilatation through NO release but, in individuals with IR, this action is impaired.20 The cause of this endothelial dysfunction in insulin-resistant states is not well understood; hypotheses include a primary defect in the endothelium causing both IR and impaired vasodilatation,20 or hyperinsulinemia leading to blunted endothelial function.36 Endothelial dysfunction is central in the development of vascular complications of DM and often occurs in concert with MAU.5 However, the role of renal endothelial function and NO availability in the progression of diabetic CKD is more complex and not entirely clear. Recent evidence suggests that abnormalities in NO production modulate renal structure and function. Early nephropathy in DM is associated with increased intrarenal NO production, whereas advanced nephropathy associated with severe proteinuria and renal function decline is related to a state of progressive NO deficiency caused by various factors.37 From this perspective, IR could promote CKD progression through renal endothelial dysfunction, but many aspects of this association need to be further elucidated.

Oxidant Stress. While hyperglycemia is a well known cause of oxidant stress, oxidant stress occurs in animal models of IR, and this increase in oxidative stress exerts negative effects on insulin action.38 The resulting hyperinsulinemia in insulin-resistant states has been proposed to further enhance oxidant stress by its effects on antioxidative enzymes and on free radical generators.39 Studies have shown increased prevalence of oxidant stress both in patients with early and overt nephropathy,40,41 thus indicating oxidant injury as a potential contributor in the progression of CKD and the decrease in NO production and availability.37 Therefore, IR and hyperinsulinemia may be linked with CKD through an increase in oxidant stress (Figure 2).


Figure 2. Schematic of the mesangial cell structural relationships with other glomerular cells and the effects of insulin. EC=endothelial cell; RAAS=renin-angiotensin-aldosterone system; BM=basement membrane; NADPH=nicotinamide adenine dinucleotide phosphate, reduced form; ECM=extracellular matrix. Adapted from Bakris GL, Walsh M F, Sowers JR. Endothelium/ mesangium interactions: role of insulin-like growth factors. In: Sowers JR, ed. Endocrinology of the Vasculature. Totowa, NJ: Humana; 1996:341–356.

Increases in Plasminogen Activator Inhibitor Type 1. Another possible mechanism by which the CMS may contribute to the progression of CKD is via increases in plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the primary physiologic inhibitor of plasminogen activation in vivo, and elevated plasma PAI-1 levels have long been proposed to contribute to the insulin resistance syndrome.42 In the normal kidney, PAI-1 is not expressed, but it is strongly induced in various forms of kidney diseases that lead to renal failure.43 Several experimental and clinical studies support a specific role for PAI-1 in the renal fibrogenic process of diabetic nephropathy. In particular, PAI-1 as the main inhibitor of plasminogen activation, apart from fibrinolysis, also inhibits plasmin-mediated matrix metalloproteinase activation.43 Matrix metalloproteinases are normally responsible for extracellular matrix degradation, and their inhibition leads to extracellular matrix expansion and renal fibrosis.44 Inhibition of PAI-1 activity, or of PAI-1 synthesis, has provided promising results for the prevention of renal fibrosis in vitro.43


  1. Top of page
  2. Abstract
  3. Pathophysiology
  4. Epidemiology
  5. Conclusions
  6. References

Associations of IR and Insulin With MAU and CKD. Many early small case-control studies in subjects with various components of the CMS investigated the association among the underlying disorder of the CMS, IR, and MAU. These studies were primarily designed to examine whether MAU was another component of the syndrome. With few exceptions, IR was significantly higher in microalbuminuric than in normoalbuminuric patients with various concomitant conditions of various origins.45,46 In cross-sectional studies, a similar trend was observed. In 982 nondiabetic subjects from the cohort of the Insulin Resistance Atherosclerosis Study,47 an investigative group showed that subjects with MAU had lower insulin sensitivity and higher fasting insulin concentrations compared with subjects without MAU. In regression analysis, an increasing degree of insulin sensitivity was related to a decreasing prevalence of MAU (odds ratio [OR], 0.86).47 In a recent study in 712 patients with DM, ACR was independently related to the homeostasis model assessment of IR (HOMA-IR) index.48

Some studies have also examined cross-sectional and prospective associations between MAU and hyperinsulinemia. In a small prospective study in patients with DM, serum insulin concentration at baseline independently and significantly predicted the UAE rate after 6 years of follow-up.49 In 497 clinically healthy, nondiabetic Koreans, those with MAU had higher levels of fasting insulin than those with normoalbuminuria and, in multiple logistic regression analyses, fasting insulin and systolic BP were the only variables independently associated with MAU.50 In a subsequent study from the same group in 1006 Koreans, subjects with MAU had higher fasting plasma insulin and proinsulin levels, while in multiple regression analyses, fasting insulin was independently related to UAE rate and hyperinsulinemia was independently associated with the presence of MAU.51

Other studies however, did not confirm these associations. In two populations with high risk of DM, Wanigelas from Papua New Guinea and Nauruans of the South Pacific, the relationships among UAE and markers of IR were inconsistent in most groups and were no longer significant after adjusting for fasting glucose and body mass index (BMI).52 In 271 never-treated, nondiabetic, uncomplicated hypertensive Caucasian men, the HOMA-IR index and insulin levels did not differ across ascending urine albumin quartiles, whereas BMI and BP were significantly greater in the upper compared with the lower quartiles.53

As far as the relationship between IR and CKD is concerned, in a case-control study in Japanese subjects, there was no significant difference in insulin sensitivity (measured with the clamp technique) among patients with DM with normoalbuminuria, microalbuminuria or macroalbuminuria. However, a fourth group of patients who had DM with CKD (serum creatinine levels >2.0 mg/dL) demonstrated more than two times lower insulin sensitivity than the normoalbuminuric group.54 In another case-control study, insulin sensitivity measured with the clamp technique was lower in nondiabetic patients with CKD than in healthy controls. Moreover, in CKD patients there is a positive correlation between insulin sensitivity and creatinine clearance.55 A recent study including 227 nondiabetic patients with CKD and different degrees of renal function and 76 matched healthy controls showed that the HOMA-IR index was also markedly higher in CKD patients than in healthy subjects. However, HOMA-IR in CKD patients was significantly correlated with BMI, triglycerides, and age, but not with the level of GFR.56

Investigators examined the relationship of fasting serum insulin, glycated hemoglobin (HbA1c), and HOMA-IR index to risk of CKD in a subgroup of the Third National Health and Nutrition Examination Survey (NHANES III) population, including 6453 adult individuals without DM.57 The prevalence of CKD was significantly and progressively higher with increasing levels of serum insulin, HbA1c, and HOMA-IR. After adjustment for potential confounders, the ORs of CKD for the highest compared with the lowest quartile were 4.03, 2.67, and 2.65 for serum insulin, HbA1c levels, and HOMA-IR, respectively. Furthermore, for one SD higher level of serum insulin, HbA1c, and HOMA-IR, the increases in the risk of CKD were 35%, 69%, and 30%, respectively. These findings support the notion that IR and concomitant hyperinsulinemia are present in CKD patients without DM. However, this analysis cannot separate the effect on the development of CKD of the two above factors from that of blood glucose levels.

Associations of the CMS With MAU and CKD. Numerous observational studies have examined the relationship between MAU, or CKD, and either the major components of CMS or the syndrome as a single entity, defined with the use of different diagnostic tools (Table). In early case-control studies, UAE was found higher in patients with many features of the CMS, and vice versa,58 but since no regression analyses were applied to adjust for possible confounders, the conclusions that can be drawn from those studies are limited.

Table Table.  Cardiometabolic Syndrome Manifestations Associated With Cardiovascular Disease
Clinical components of cardiometabolic syndrome
 Insulin resistance/hyperinsulinemia
 Visceral obesity
Additional manifestations
 Chronic kidney disease
 Increased serum apolipoprotein B levels
 Small, dense low-density lipoprotein cholesterol particles
 Increased plasminogen activator inhibitor/plasminogen activator ratio
 Increased serum fibrinogen levels
 Increased production of interleukin-6
 Increased systolic and pulse pressure
 Premature atherosclerosis
 Enhanced tissue renin-angiotensin-aldosterone system
 Salt sensitivity
 Endothelial dysfunction

Data from cross-sectional studies performed in subjects with various concomitant conditions are more interesting. One such study examined the effects of the factors included in the “deadly quartet” described by Kaplan in 198959 (upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension) on overnight UAE ratios in 317 patients with DM. In logistic regression analyses controlling for possible confounders, elevated HbA1c, or the addition of one component of the deadly quartet, to pure DM doubled or tripled the odds of an elevated UAE ratio. The addition of two components to DM further increased the ORs, while the presence of DM and all three factors were associated with an OR of 9.34 for elevated UAE.60 Another cross-sectional study examined associations of MAU and macroalbuminuria with the CMS among Australian Aboriginal people and showed highly significant linear associations of both microalbuminuria and macroalbuminuria with an increasing number of components of the syndrome.61 Among people with none, one, two, and three to five of these components, the prevalence of MAU was 16%, 20%, 36%, and 32%, and the prevalence of macroalbuminuria was 2%, 6%, 12%, and 32%, respectively. However, MAU was independently associated only with hypertension and DM, and macroalbuminuria was independently associated only with hypertension, DM, abdominal obesity, and less strongly with IR—findings indicating that hypertension and DM were the major contributors to high rates of albuminuria in this population.

In the sixth examination (1995–1998) of the Framingham Offspring Study,62 urine ACR was measured in 1592 subjects and categorized as having none, one, two, or all three of the phenotypes of IR syndrome they used: impaired glucose tolerance, hypertension, and/or a central metabolic syndrome (two or more traits of obesity, dyslipidemia, or hyperinsulinemia). The groups of participants with all three phenotypes of the syndrome had higher age- and sex-adjusted ACRs and a greater proportion of ACR >30 mg/g than those with no phenotypes. Moreover, groups with two or three phenotypes of the syndrome had higher ACRs and a greater proportion of subjects with ACR >30 mg/g than groups with none or one of the phenotypes—and groups with hyperinsulinemia tended to have a greater proportion of subjects with ACR >30 mg/g compared with those without hyperinsulinemia.62 Another investigative group explored the association between MAU and the IR syndrome in 934 nondiabetic Native Americans. After controlling for possible confounders, the OR for MAU was 1.8 for one IR syndrome component, 1.8 for two, and 2.3 for three or more, compared with the presence of no syndrome components.63

As with IR, however, not all the studies examining the relationship between the CMS and MAU documented a close association. A Dutch study used an age-, sex- and glucose tolerance-stratified random sample of the 50–75-year-old general population (n=622) to examine the relationship between MAU and several variables related to the syndrome.64 In multiple logistic regression analyses, MAU showed independent associations with hypertension, DM, and waist-to-hip ratio, but no associations with impaired glucose tolerance, hyperinsulinemia, IR, or dyslipidemia. The authors concluded that in this population, MAU was likely a complication of hypertension and DM, and not an integral part of the IR syndrome. Another study examined this relationship in 1031 young adults (61% Caucasian, 39% African American) from the population of the Bogalusa Heart Study.65 After controlling for age and gender, African Americans with MAU had higher systolic and diastolic B P, prevalence of hypertension, and HDL cholesterol than those without MAU, whereas Caucasians showed no such associations. In both races, none of the other variables of the CMS measured (BMI, waist circumference, triglycerides, glucose, insulin, HOMA-IR index, and uric acid) displayed any relation to MAU, suggesting that MAU is not necessarily an intrinsic component of the syndrome.

In recent years, studies examining the relationship between the CMS and CKD have also been released. In further analyses in subsamples of the NHANES III population, including more than 6000 adult subjects aged 20 years and older, investigators observed that the syndrome, defined according to the NCEP/ATP III criteria, was associated with higher risk of both MAU and CKD.66 In particular, the multivariate-adjusted OR of MAU in participants with the CMS compared with participants without it was 1.89 and compared with participants with no or one component of the syndrome, those with three, four, and five components had ORs for MAU of 1.62, 2.45, and 3.19, respectively. Moreover, in participants with the syndrome, the OR of CKD was 2.60 compared with those without it, whereas subjects with two, three, four, and five components had ORs of 2.21, 3.38, 4.23, and 5.85, respectively, compared with participants with no or one component. In multivariate models, however, elevated BP and plasma glucose levels are associated with an increased OR of MAU, whereas elevated B P, low HDL cholesterol, high triglycerides, and abdominal obesity are each associated with an increased OR of CKD,66 thus making it difficult for this analysis to separate the effects of the CMS from those of the individual components on the development of MAU and CKD.

Yet another cross-sectional analysis, a nested cohort of the NHANES III database including more than 7300 participants, examined the prevalence of non-traditional CVD risk factors, including CKD, across DM status and for persons with and without the CMS. After adjustment for multiple confounders, the presence of CMS was again significantly associated with CKD (OR, 2.27).67 A more recent study examined the association of the syndrome defined according to the NCEP/ATP III criteria with diabetic nephropathy in 2415 Finnish patients with type 1 DM. Participants were classified as having a normal UAE rate, MAU, macroalbuminuria, or end-stage renal disease, and the prevalence of the syndrome rose significantly from 28% to 44%, 62%, and 68%, respectively. Moreover, patients with the CMS had an almost four times higher risk of diabetic nephropathy, and each of the separate components of the CMS was independently associated with diabetic nephropathy.68

Finally, the association between the CMS and CKD was also examined in two recent prospective studies.69,70 In the first, including 10,096 nondiabetic subjects with normal baseline kidney function from the original cohort of the Atherosclerosis Risk in Communities (ARIC) study, the presence of the CMS was again associated with a higher risk of CKD after 9 years of follow-up.69 Participants who fulfilled the NCEP/ ATP III criteria for the CMS at baseline had a 43% greater risk of developing CKD than those without it. Compared with participants with no components of the syndrome, those with one, two, three, four, or five components of it had an OR for CKD of 1.13, 1.53, 1.75, 1.84, and 2.45, respectively. Moreover, after adjustment for the subsequent development of DM and hypertension during the 9 years of follow-up, the participants with the CMS at baseline still had a 24% greater risk of developing CKD compared with those without it.69 The second study included subjects without CKD from the Framingham Heart Study offspring cohort and followed them for an average of 7 years for development of CKD. After adjusting for multiple confounders among participants without DM at baseline, the presence of the syndrome was almost significantly associated with the development of CKD during the follow-up period (OR, 1.46; p=0.06).70


  1. Top of page
  2. Abstract
  3. Pathophysiology
  4. Epidemiology
  5. Conclusions
  6. References

Mounting evidence supports the hypothesis that IR and compensatory hyperinsulinemia promote renal injury through various potential pathways. In human studies, IR and hyperinsulinemia have been associated with increased glomerular permeability to albumin,14 intraglomerular pressure, and UAE.18 Insulin has been shown to directly promote mesangial cell proliferation and extracellular matrix protein production25 and to increase the production of other growth factors, such as IGF-122 and TGF-β26,27 that play a central role in the mitogenic and fibrotic processes in diabetic nephropathy. Insulin is also known to interfere with the RAAS, i.e., enhancing the action of Ang II in mesangial cells.26,30 Moreover, the endothelial dysfunction or the oxidant stress present in insulin-resistant states, as well as the elevation of PAI-1 levels, could be additional mechanisms linking IR with CKD.37,43,71

Most of the early observational studies examining the relationship between IR or hyperinsulinemia and MAU, as an index of renal injury, have found an independent association between these parameters.45–51 In the majority of the studies investigating the association of the CMS with MAU, both the level of UAE and the prevalence of MAU increased with the number of components of the syndrome.60–63 These observational data strongly indicate that MAU clusters with the other components of the syndrome. However, due to the nature of the information coming from case-control and cross-sectional studies, the above data cannot establish causality between IR, or hyperinsulinemia, and the development of MAU. In addition, a proportion of the relevant studies did not confirm the above associations,52,53 and perhaps the relationship between IR and MAU is not homogeneous in both sexes48 and in all populations.52,65 Since prospective studies on the field are not available, it seems that strict conclusions cannot be made in regard to MAU and IR.

As far as IR and CKD are concerned, although the available data are from a limited number of case-control54,55,72 and cross-sectional studies56,57 and thus cannot be conclusive, they also indicate a relationship between IR and CKD. On the other hand, information from cross-sectional66–68 but also prospective studies69 strongly suggests that the presence of the syndrome is significantly associated with CKD and the relative risk for CKD increases with the number of the components of the syndrome present in one individual.

In spite of the existence of several potential pathophysiologic pathways linking IR with renal injury, the question arises as to whether the presence of the CMS is associated with a risk of CKD beyond its individual components, which are already known risk factors for CKD (e.g., hypertension, DM, obesity). A similar question regarding the association between the syndrome and CVD risk, for which much more information is available, was recently raised in a joint statement from the American Diabetes Association (ADA)/ European Association for the Study of Diabetes (EASD).73 In this statement, the authors concluded that the CVD risk associated with the syndrome is no greater than the sum of its parts. This is undoubtedly related to the fact that the underlying pathophysiology of the syndrome is still not clear and therefore the recognition of a syndrome as a single entity with specific and well-defined components is difficult. This is reflective of the existence today of about seven major definitions for the same concept, among which there are important differences.1 Therefore, further research is needed to fully clarify the existence of the CMS as a single entity, and after that, the development of a single diagnostic tool is necessary to examine the prognostic value of the CMS for CKD, as well as CVD. In parallel, new experimental studies should elucidate the speculated mechanisms that connect IR and hyperinsulinemia with renal injury. Until then, clinicians must always bear in mind that certain important CKD risk factors undoubtedly occur together more often than expected by chance in a broad concept of a “syndrome” and, if one of these risk factors is present, the patient should be evaluated for the presence of the rest and aggressively treated.


  1. Top of page
  2. Abstract
  3. Pathophysiology
  4. Epidemiology
  5. Conclusions
  6. References
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