Renal Manifestations in The Metabolic Syndrome

Renal Manifestations in the Metabolic
Syndrome
1. Francesco Locatelli,
2. Pietro Pozzoni and
3. Lucia Del Vecchio
+ Author Affiliations
1. Department of Nephrology and Dialysis, A. Manzoni Hospital, Lecco, Italy
1. Address correspondence to:
Prof. Francesco Locatelli, Department of Nephrology and Dialysis, A. Manzoni Hospital, Via dellEremo 9/11, 23900
Lecco, Italy. Phone: +39-0341-489850; Fax: +39-0341-489860; E-mail: nefrologia@ospedale.lecco.it
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Abstract
The metabolic syndrome, which is characterized by obesity, serum lipid profile alterations, hypertension, and fasting
hyperglycemia, is very common in developed countries, and its prevalence is likely to increase. Chronic kidney disease
(CKD) also has become a significant public health problem because it affects a considerable proportion of the adult
population and is a major risk factor for cardiovascular disease and premature death. Although it is widely known that the
metabolic syndrome is a major risk factor for the development of type 2 diabetes and cardiovascular disease, its precise
relationship with the risk for renal impairment only recently has been clarified: Patients with the metabolic syndrome are at
significantly higher risk for microalbuminuria and/or CKD, and the level of risk is related to the number of components of
the syndrome itself. Although it is difficult to discriminate the detrimental renal effects of the metabolic syndrome from
those of hypertension and impaired glucose metabolism, its other aspects (particularly obesity) may favor independently the
development of renal abnormalities and may be considered new modifiable risk factors for CKD. These observations provide
a rationale for intervention studies that aim to verify whether treating the many components of the metabolic syndrome can
effectively prevent the development and progression of renal damage.
The metabolic syndrome (also known as syndrome X or the insulin resistance syndrome) is a complex pattern
of disorders that were described for the first time by Reaven in 1988 (1) and whose main features consist of
abdominal obesity, hypertriglyceridemia, low HDL cholesterol levels, high BP, and high fasting blood glucose
levels. Although somewhat different definitions of the syndrome have been proposed since its first description,
the guidelines of the 2001 National Cholesterol Education ProgramAdult Treatment Panel III (2) now are widely
used to identify it (Table 1), although a recent report from the National Heart, Lung, and Blood Institute and the
American Heart Association (NHLBI/AHA) (3) recommended lowering the cutoff point for fasting blood glucose
levels and abdominal obesity in men and proposed diagnosing the syndrome in the presence of only two of the
defined criteria (Table 1). However, it cannot be excluded that the identification of additional risk factors, such as
high C-reactive protein levels (4), soon will lead to a broader definition of the syndrome. Pathogenetically, it is
thought that insulin resistance plays a key role in its development, as is suggested by a number of observations
linking insulin resistance (clinically defined by the detection of abnormally high plasma insulin concentrations)
with each of the syndromes components (5).
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Table 1.
NCEP-ATP III diagnostic criteria for metabolic syndrome and revised criteria as proposed by NHLBI/AHA a
The metabolic syndrome is very common in developed countries, and its prevalence is expected to become even
higher in the near future, together with the rapidly increasing prevalence of obesity. For many years, there were
few data concerning the relationship between the metabolic syndrome and the risk for developing renal
abnormalities; however, recent epidemiologic analyses have found that patients with the syndrome also are at
high risk for microalbuminuria and/or chronic kidney disease (CKD), thereby allowing the identification of a target
population that may benefit from therapeutic strategies that aim to prevent the development of renal
manifestations.
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Metabolic Syndrome and CKD: Two Major Public Health Problems

The epidemiologic impact of the metabolic syndrome was evaluated in 8814 adults who were aged 20 yr or more in the
United States and participated in the Third National Health and Nutrition Examination Survey (NHANES III) between 1988
and 1994 (6). The overall age-adjusted prevalence of the metabolic syndrome in this population (as defined by the 2001
National Cholesterol Education ProgramAdult Treatment Panel III criteria) was approximately 24%, with a clear age-
dependent increase (6.7% in those aged 20 yr and up to 42% in those aged >70 yr) (6). Applying these results to the US
resident population, it can be estimated that 47 million US residents who were 20 yr or older satisfied the diagnostic criteria
for the metabolic syndrome in 2000.
A number of conditions have been associated with an increased risk for the metabolic syndrome; increased body weight
plays the most important role. The observed prevalence of the metabolic syndrome in NHANES III was 5% among the
subjects of normal weight, 22% among the overweight, and 60% among the obese (7). A Framingham Heart Study report
indicated that a weight increase of 2.25 kg over a period of 16 yr was associated with an up to 45% increased risk for
developing the metabolic syndrome (8), and it was shown recently that each 11-cm increase in waist circumference is
associated with an adjusted 80% increased risk for developing the syndrome within 5 yr (9). The rapidly increasing
prevalence of obesity in the adult US population (10) suggests that the current number of individuals who have the metabolic
syndrome very probably is much higher than that estimated on the basis of the NHANES III analysis. In fact, a recent
comparison of NHANES III and NHANES 1999 to 2000 data found that the overall age-adjusted prevalence of the syndrome
increased from 24 to 27% (32% when using a glucose cutoff point of 100 mg/dl) of the 1677 individuals who participated
in NHANES 1999 to 2000, with the percentage increase being particularly high (23.5%) among women (11). On the basis
of these prevalence estimates and using the revised NHLBI/AHA definition, it is possible to estimate that at least 64 million
adults in the United States were actually affected by the metabolic syndrome in 2000.
Like the metabolic syndrome, CKD is increasingly emerging as a major public health problem, although it is still probably
underestimated because widely accepted definitions of the disease only recently have been developed and only a few
epidemiologic analyses have been undertaken. A recent analysis of a large nationally representative sample of US adults
that was performed between 1999 and 2000 found that the prevalence of moderate to severe kidney dysfunction (defined as
an estimated GFR of 15 to 59 ml/min per 1.73 m2) was 4.4%, whereas the prevalence of mildly decreased kidney function
(an estimated GFR of 60 to 89 ml/min per 1.73 m2, corresponding to stage 2 CKD according to the Kidney Disease Outcomes
Quality Initiative Clinical Practice Guidelines [12]) was 36.3%, approximately 5% more than that found in a similar survey
performed between 1989 and 1994 (13). This means that >40% of the US adult population (>75 million people) can be
expected to have CKD, even when patients with detectable kidney damage but without a reduced GFR are excluded.
The consequences of the increasing epidemiology of CKD are devastating, not only for the patients themselves but also in
terms of the economic demands on society. CKD often is characterized by progression to ESRD, a condition that requires
renal replacement treatment (RRT) if the patients are to survive and thus accounts for a disproportionate part of health care
resources. The prevalence of RRT in the United States increased by 97% from 1991 to 2000, and it has been estimated that
an additional 60% increase will occur between 2001 and 2010, when it is expected that 650,000 patients will require RRT
(14). In addition to being a precursor of ESRD, CKD is a major risk factor for cardiovascular disease, the risk for which
increases with the progressive decrease in kidney function (15). In relation to this, a recent survey of almost 28,000 patients
who had CKD and were followed for up to 66 mo surprisingly found that such patients are at greater risk for dying (mainly
because of cardiovascular disease) than developing ESRD, regardless of the stage of CKD at the time of first evaluation
(16).
Metabolic Syndrome and Risk for Developing Renal Abnormalities

Although the metabolic syndrome has been associated with a number of clinical conditions, including the subsequent
development of type 2 diabetes, cardiovascular disease, fatty liver disease, polycystic ovary syndrome, and sleep-disordered
breathing, as well as with increased all-cause and cardiovascular mortality (1720), few data are available concerning its
relationship with the risk for developing renal abnormalities, particularly CKD and microalbuminuria. Despite this, some
groups have recently examined the association between the syndrome and renal impairment and found that affected
individuals are at increased risk for presenting renal manifestations. A cross-sectional survey of nondiabetic native
Americans that was conducted by Hoehner et al.(21) found that, after controlling for social, demographic, and comorbidity
factors, the patients with one to two and those with three or more traits were, respectively, 80 and 130% more likely to have
microalbuminuria than those without the syndrome. Chen et al. (22) extracted data from the NHANES III database of >6000
adults and found that the multivariate-adjusted risk for both microalbuminuria and CKD (defined as a GFR of <60 ml/min
per 1.73 m2) was significantly higher in those with than in those without the metabolic syndrome and that the risk increased
progressively with the number of the syndromes components detected in each patient.
Although the results of these studies suggest that there is a close association between the metabolic syndrome and renal
dysfunction, it is difficult to draw any definitive conclusion concerning a cause-and-effect relationship because of the
complexity of their interrelationships. First, many patients with the metabolic syndrome are hypertensive and/or have
diabetes (i.e., affected by at least one widely known risk factor for the development and progression of CKD). For example,
Chen et al. (22) found that hypertension and fasting plasma glucose levels of >110 mg/dl were the individual traits of the
syndrome that are associated with the greatest risk for microalbuminuria and (with the exception of hyperglycemia) a low
GFR. However, some data suggest that other aspects of the metabolic syndrome may play an independent role in promoting
renal damage. Chen et al. (22) found that reduced HDL cholesterol or high triglyceride levels were independently associated
with a significantly increased risk for CKD, strengthening the results of a previous prospective study by Muntner et al.(23),
who found that the same serum lipid abnormalities predicted the development of renal impairment in patients with normal
renal function at baseline.
A number of findings also indicate obesity (a cardinal feature of the metabolic syndrome) as an independent factor for
causing renal dysfunction. The multivariate analysis made by Chen et al. (22) showed that the risk for being affected by
CKD was more than twice as high in patients with an increased waist circumference than in those without, suggesting that
obesity may be an independent risk factor for CKD. The role of obesity as a potentially important cause of CKD also was
indicated in a community-based analysis of a large sample of Japanese patients that was conducted by Iseki et al. (24), who
found that the risk for developing ESRD was significantly higher in men with an increased body mass index, even after
adjustments for BP and proteinuria, two overweight-related factors that may have accounted for a nonindependent
detrimental effect of obesity on renal function. Moreover, since the first description of an association between massive
obesity and nephrotic proteinuria in 1974 (25), a specific histopathologic pattern characterized by glomerulomegaly, in many
cases accompanied by focal segmental glomerulosclerosis, has been described repeatedly in obese patients without any other
defined primary or secondary glomerular diseases (including diabetic nephropathy, hypertensive nephrosclerosis, and
secondary focal segmental glomerulosclerosis) and now is referred to as obesity-related glomerulopathy (26). At the
clinical level, this glomerulopathy typically is associated with overt proteinuria (frequently within the nephrotic range) and
renal insufficiency in nearly half of the patients and often is characterized by a progressive clinical course (26). It also is
worth noting that a 10-fold increase in the biopsy incidence of this condition was observed over a period of 15 yr (from
0.2% of all renal biopsies in 1986 to 1990 to 2.0% in 1996 to 2000) (26), and this reflects the epidemiologic data showing
an increase in the prevalence of obesity in the general population during the same period (27).
Although the exact mechanisms that link obesity and renal damage have not yet been elucidated completely, it can be
speculated that at least some of the many inflammatory cytokines that are secreted by adipose tissue, including leptin, IL-6,
TNF-, and adiponectin, may be involved at least partially in promoting renal impairment (28); in particular, the high plasma
leptin levels that are observed in obesity may predispose to glomerulosclerosis as a result of the intrarenal upregulation of
TGF- (29). However, it is thought that other obesity-related factors, such as altered renal hemodynamics (partially as a
result of high dietary protein intake), hyperlipidemia, excess renal sodium reabsorption, activation of the renin-angiotensin
and sympathetic nervous systems, and physical compression of the kidneys by adipose tissue, may lead to complex
interactions between intrarenal physical forces, neurohumoral factors, and local mediators (growth factors and cytokines)
that ultimately give rise to glomerular hyperfiltration, glomerular cell proliferation, matrix accumulation, and, finally,
glomerulosclerosis and the loss of nephrons (30).
Potential Strategies for Preventing Renal Damage in Metabolic Syndrome

The observed association between the metabolic syndrome and the risk for renal dysfunction raises the question of whether
correcting one or more of the syndromes many features may effectively prevent CKD. Although the aggressive treatment
of all metabolic alterations in such patients may be warranted to prevent the development of extrarenal complications, it is
unclear whether this may prevent renal impairment. It has been shown that intensive BP and blood glucose control effectively
prevents the development of microalbuminuria and overt nephropathy in patients with diabetes (3134), but the extent to
which this is true also in patients with the metabolic syndrome needs to be confirmed by appropriate clinical trials.
Furthermore, the nephroprotective superiority of angiotensin-converting enzyme inhibitors over other antihypertensive drug
classes that has been suggested by a number of clinical trials involving patients with diabetes (35,36) still needs to be
demonstrated in the context of the metabolic syndrome. Some recent studies, including a meta-analysis of clinical trials,
have shown the effectiveness of lipid-lowering treatments in decreasing proteinuria and slowing the rate of the decline in
GFR in patients with CKD (37), but whether they also are effective in preventing the onset of renal impairment in patients
with normal renal function is still unclear. Finally, although there is no doubt that all obese individuals should be encouraged
to undertake physical activity and change their eating habits, the significant impact of weight loss on renal outcomes
suggested by preliminary observations (38) still needs to be demonstrated by properly designed clinical trials.
Consequently, because of the lack of evidence from clinical trials specifically involving patients with the metabolic
syndrome, it is still unclear whether therapeutic interventions that aim to correct the various abnormalities of the metabolic
syndrome (possibly using a multifactorial approach) can actually prevent the development and/or progression of renal
damage. Until such trials are conducted, the only available preventive strategy consists of considering patients with the
metabolic syndrome as a subset of patients who are at very high risk for developing microalbuminuria and/or CKD and who
therefore require close monitoring to ensure the early recognition and treatment of subsequent renal abnormalities and their
related complications.
Conclusion
A close association has been found between the metabolic syndrome and the risk for developing renal damage, clinically
expressed in the form of microalbuminuria and/or CKD. This finding raises a major clinical and public health concern
because both the metabolic syndrome and CKD are increasingly common disorders in all developed countries. Although it
is difficult to discern the detrimental renal effects of the metabolic syndrome from those of hypertension and impaired
glucose metabolism, various experimental and epidemiologic data suggest that other aspects of the syndrome (particularly
obesity) may favor independently the development of renal abnormalities and thus become newly recognized (but no less
important) modifiable risk factors for CKD in addition to diabetes and hypertension.
Despite the close association between the metabolic syndrome and renal damage, it is still unclear whether and to what
extent treating patients with the metabolic syndrome will prevent the development and progression of CKD. Given the
epidemic nature of the problem, the planning of clinical trials that aim to verify whether treating the many components of
the metabolic syndrome may effectively prevent renal impairment should be considered a research priority.
Metabolic syndrome and chronic kidney disease: Current status

and future directions
G V Ramesh Prasad
Author information Article notes Copyright and License information
This article has been cited by other articles in PMC.
Abstract
Core tip: Metabolic syndrome is associated with chronic kidney disease but its role in chronic
kidney disease incidence and progression has not been established. When both these conditions
are present, management should be targeted to individual risk factors for kidney disease
progression and cardiovascular disease.
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INTRODUCTION
Metabolic syndrome (MetS), previously called syndrome X is a term in popular use for the
past quarter century, having first been described in 1988 by Reaven[1] to denote a combination
of selected, widely prevalent cardiovascular disease (CVD)-related risk factors. Although the
general principle behind using the MetS concept is to denote an increased CVD or diabetes risk,
the MetS definition itself is ambiguous through the inclusion of different criteria and assigning
them different levels of importance[2-6]. Furthermore, some MetS definitions have been revised
over the years, leading to the multiple definitions in current use[2-6]. The four most common
definitions are summarized in Table Table1.1. Nonetheless, the general concept is that a MetS
patient will have some combination of conditions, among which are insulin resistance or
hyperglycemia, dyslipidemia, hypertension, and obesity. Identifying such combinations should
add meaningfully to the long-term clinical management of MetS.
Table 1
Criteria in definitions of the metabolic syndrome[2-6]
MetS is known to be with increased CVD risk in the general population[7,8]. It has also been
associated with incident overt type 2 diabetes[9,10], in those previously without diabetes
contributing to their MetS definition. Other MetS associations include non-alcoholic fatty liver
disease[11], and hyperuricemia[12]. In addition, the association of MetS with chronic kidney
disease (CKD) is receiving increased attention in selected populations[13-15]. CKD however is
also a long-term illness, just like MetS, and often progresses over many years from mild
reductions in glomerular filtration rate to more advanced pre-uremic states and eventual renal
replacement therapy. CKD is asymptomatic until very late in its course, when symptoms such as
fatigue, nausea and anorexia, itching, cramping and muscle twitching, and edema occur. The
relationship between MetS and CKD is typically approached as snapshots in isolation during
each CKD stage. The major purpose of this review is to approach the MetS-CKD relationship
from the standpoint of each stage as points along the CKD spectrum where the diagnosis of
MetS may be raised. This may help to better determine whether MetS is either in fact part of the
etiology of CKD, the end result of risk factors common to both MetS and CKD, or a completely
unrelated entity.
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METABOLIC SYNDROME AS AN ASSOCIATION WITH CKD

Many studies associate MetS with CKD. This is perhaps the lowest level of evidence for
causation. Each component of MetS has been associated with both CKD incidence and
progression. MetS and CKD share a complex, bidirectional relationship. Obesity is associated
with CKD[16-18]. Both obesity and CKD are increasing in prevalence, at least in the United
States[19]. The earliest stages of CKD are typically missed because of its asymptomatic nature
and lack of screening in annual physical examinations. It is therefore difficult to assemble
sufficiently large cohorts known to be without CKD based on the appropriate baseline data and
then follow them over a sufficient length of time in order to determine whether they have
developed early (i.e., stages I or II) CKD or not. This will require measurements of renal
function in the normal range that tools such as the Modification of Diet in Renal Disease
(MDRD) equations[20] were not designed to handle.
A meta-analysis of eleven studies[13,14,21-29] of 30146 subjects reported that MetS was
associated with development of an estimated GFR (eGFR) < 60 mL/min per 1.73 m2, (Stage III
CKD) with odds ratio (OR) 1.55 (95%CI: 1.34-1.80)[19]. Many of these studies specifically
excluded those with diabetes[21,22,26-28], which is not only a potential component of MetS, but
a major cause of CKD. Not included also was a study[15] from the National Health and Nutrition
Examination Survey (NHANES III) database of 7800 subjects followed for 21 years, who having
had normal renal function at baseline, were found to have an OR of 2.6 (95%CI: 1.68-4.03) for
CKD if MetS was present. These authors[15] also determined a relationship between the number
of MetS components present and risk. Sometimes, surrogate markers of CKD such as
microalbuminuria or proteinuria are used instead[13,22-23,29] using varying definitions for both
protein loss and MetS[19]. A small number of studies showed an increase in albumin or protein
excretion associated with MetS[19]. Another study from the NHANES database also showed an
increase in microalbuminuria with MetS[30].
Despite the large number of such associative studies between MetS and CKD, causality remains
unproven[19]. The time-to-onset of both MetS and CKD are equally difficult to determine. Since
individual components of MetS are prone to fluctuating values and are sensitive to unmeasured
lifestyle modifications, medication effects, or acute illness, it is possible that some proportion of
subjects experience change with respect to their MetS status overall during follow-up. Similar
changes may occur with eGFR and a CKD diagnosis that is based on arbitrary eGFR cut-offs.
Over-simplification of MetS criteria (such as using only body mass index (BMI) while ignoring
waist and hip circumference, or systematically ignoring ethnicity), further limits making firm
conclusions about associations. Obesity and CKD are increasing in prevalence[19] and this could
obfuscate the relationship between two common disease entities. Investigation at the level of the
individual subject may help shed light on the association of MetS with CKD.
A histopathology-based cross-sectional report of 146 patients undergoing nephrectomy showed a
higher prevalence of CKD features, including global as well as segmental glomerulosclerosis in
those with MetS. Other features noted included a higher prevalence of tubular atrophy,
interstitial fibrosis, and arterial sclerosis[31]. Loss of renal function post-nephrectomy was more
pronounced[31], but sequential biopsy studies are of course not feasible. Another approach is to
study intra-renal hemodynamics by ultrasound, wherein renal parenchymal damage in MetS may
be reflected by increased intra-renal resistive indices[32]. These novel studies may help us
progress beyond making simple associations, but will need prospective evaluation in larger
numbers of patients for validation. A summary of important renal associations with MetS is
provided in Table Table22.
Table 2
Renal associations of metabolic syndrome
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METABOLIC SYNDROME AS AN ETIOLOGY OF CKD

More convincing than association alone would be a mechanistic explanation for MetS as a cause
for CKD. The search for mechanisms is essential to remove the black boxes that exist along
any proposed causal pathway between MetS and CKD. It may be all one linear mechanism that
leads from MetS to CKD, or it may equally likely be a number of distinct but inter-dependent
mechanisms set in motion by MetS and operating simultaneously to result in significant renal
impairment. The mechanisms leading to MetS may also be the same ones causing CKD. In this
context, there may be a perfect storm of multiple risk factors including insulin resistance,
inflammation, abnormal lipid metabolism, and hypertension leading to increased expression of
pro-fibrotic factors[33]. Finally, we still cannot exclude chance associations between two
otherwise common diseases.
Insulin resistance may be the most important MetS-related etiological factor for CKD. Insulin is
an anti-inflammatory hormone. Insulin resistance, which is typical of type 2 diabetes, leads to
inflammation, leading to oxidative stress and renal insufficiency[34]. Raised insulin levels
stimulate insulin-like growth factor 1 (IGF-1) production, which increases connective tissue
growth factor, thus causing fibrosis in the diabetic state[35]. Furthermore, and possibly
independently, obesity may lead to increased secretion by adipose tissue of pro-inflammatory
cytokines such as leptin, interleukin-6, and tumor necrosis factor-alpha (TNF-)[36]. Leptin may
lead to increased intra-renal expression of transforming growth factor-beta (TGF-), leading to
glomerulosclerosis[37]. It may also promote type IV collagen production[38,39]. TNF- may
lead to the production of reactive oxygen species (ROS) that can in turn lead to renal endothelial
cell dysfunction, mesangial expansion and fibrosis[40]. Anti-inflammatory hormones like
adiponectin may be reduced[36,41], contributing to insulin resistance as well. Adiponectin
deficiency is associated with vascular intima thickening and smooth muscle cell
proliferation[42]. Its vascular effects may even be independent of insulin sensitivity[43], and so
may extend to CKD. Obesity also leads to increased glomerular volume, podocyte hypertrophy,
and mesangial matrix expansion preceding CKD[44]. Triglycerides and free fatty acids may
themselves be nephrotoxic by promoting pro-inflammatory cytokine production[45]. In
association with hypertension, another MetS component, angiotensin II stimulates ROS
production, in turn decreasing nitric oxide synthase production and causing renal microvascular
injury, ischemia, and tubulointerstitial damage[46,47]. Dissecting out the relative contribution of
insulin resistance, obesity, and hypertension to these findings versus the composite of MetS
however is difficult. In this regard, the presence of early arterial hyalinosis[31] which is more
typical of diabetes but not MetS, may point towards MetS being a distinct risk factor for CKD
independent of its individual components. One more somewhat provocative hypothesis is that
hyperuricemia, not a traditional MetS component but associated with MetS[12], is a promoter
of CKD through the inhibition of nitric oxide production[48] or even recurrent
nephrolithiasis[49]. Another limitation to be pointed is that most mechanistic explanations have
been derived from animal models, and so their importance in human patients with MetS and
CKD, with their different lifespans and disease profiles remains to be demonstrated. A summary
list of possible mechanisms for CKD in MetS is shown in Table Table3.3. Studies mostly
support the direction of the relationship to be from MetS to CKD and not vice versa, but this is
unconfirmed.
Table 3
Potential mechanisms of chronic kidney disease in metabolic syndrome
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METABOLIC SYNDROME AND PROGRESSIVE CKD

Once CKD is identified, with the understanding that the definition is somewhat arbitrary,
monitoring progression becomes more straightforward. Several population-based studies have
identified MetS with CKD progression. Once stage III or IV CKD has been reached, the
presence of MetS has been associated with a hazard ratio of 1.33 (95%CI: 1.08-1.64) for end-
stage renal disease (ESRD) over a follow-up period of just 2-3 years in a cohort of over 15000
patients[50]. In particular, impaired glucose metabolism, hypertriglyceridemia, and hypertension
were associated with an increased risk of ESRD. Similarly, an incremental increase in insulin
resistance was associated with a greater rate of decline in renal function in a cohort of elderly
patients with CKD[51]. On the other hand, it was demonstrated that the relationship of MetS to
CKD may not be constant over the progression through CKD stages. In the later stages of CKD,
MetS as a risk factor for progression may become less important[52], perhaps because CKD
itself leads to rapid progression in a form of vicious circularity. Also, greater attention may be
paid to MetS in the later stages of CKD, so that its impact becomes less prominent. Another
study showed that even though MetS was associated with albuminuria, the effect of MetS on
CKD progression was independent of this[53]. This is controversial however, since proteinuria is
a known risk factor for CKD progression to ESRD and is also a component of some MetS
definitions. Despite the greater than 30% risk with MetS, adjustment for proteinuria attenuated
the risk for development of a composite endpoint of significant decrease in GFR, ESRD, or death
in the African American Study of Kidney Disease and Hypertension trial[54].
The distinction between CKD incidence and progression may be arbitrary since renal
insufficiency must first progress to the point where CKD is diagnosed at some threshold level of
renal function. If the underlying progression is left unchecked however and the new
pathophysiology of CKD becomes established, then the risk factors common to CKD and MetS
combine to accelerate CKD progression. First, obesity-related glomerular hyperfiltration could
combine with that induced by CKD itself, leading to accelerated glomerulosclerosis. Second,
inflammation and oxidative stress are worsened in CKD[55]. Hypertension and
hypertriglyceridemia are worsened[55], and insulin resistance may be promoted by the
undernourished state that can be caused by CKD as well as lead to CKD[56,57]. This
relationship is thus bidirectional. Third, this insulin resistance may combine with inflammation
to cause endoplasmic reticulum stress. According to this theory, misfolded proteins
accumulate in the lumen of the endoplasmic reticulum, suppressing insulin secretion through
phosphorylation of the insulin receptor substrate (IRS-1)[58]. Finally, insulin resistance also
worsens renal hemodynamics through increasing sodium retention, and affecting the transport of
other cations and anions[59]. Hypertension is worsened, leading to further renal damage.
Similarly, the sympathetic nervous system is activated[60], leading to unfavorable renal
hemodynamics, proteinuria, and ischemia. Proteinuria itself may lead to podocyte injury, and
eventually lead to chronic tubulointerstitial injury, thereby worsening CKD[61]. Unless
cardiovascular mortality intervenes, progression to ESRD may occur.
Role of cardiovascular disease in progression of metabolic syndrome-related CKD
Even mild CKD has been associated with increased CVD risk[62]. CVD mortality also increases
with increasing serum creatinine concentrations[62]. Advanced CKD is also a high risk situation
for cardiovascular events and mortality. In one study of stage IV or V CKD patients, MetS was
predictive of a composite of CVD mortality, acute coronary syndrome (ACS), revascularization,
non-fatal stroke, and amputation (hazard ratio 2.46, 95%CI: 1.17-5.18)[63]. In this study of 200
patients, intensive risk factor modification was not effective[63]. Coronary heart disease is
promoted by the components of MetS. Patients with both MetS and CKD exhibit greater
coronary artery plaque burden with higher lipid content, as demonstrated by intravascular
ultrasound[64]. With renal insufficiency, myocardial infarction (MI) in the context of MetS is
associated with higher mortality at one year[65]. In over 900 patients undergoing carotid
revascularization where 14% had some degree of CKD, MetS increased the risk for stroke, MI,
and death[66].
The patient with MetS and progressive CKD treads a dangerous path towards ESRD. Besides
being simply associated with CKD, MetS may also lead to CKD through a variety of
pathophysiological mechanisms. MetS may also lead to more rapid CKD once it is established.
Both MetS and CKD in turn are associated with increased risk for CVD events, and when both
occur together the effect may be additive. It stands to reason that ACS and MI are major
contributors to all-cause mortality seen when these two common conditions are combined,
regardless of whether MetS leads to CKD or both are independently acquired. Furthermore, it is
likely that ACS and MI themselves lead to acute kidney injury and acceleration of CKD. This
could happen as a result of acute shifts in effective intravascular volume or contrast exposure, for
example. Increased mortality effectively prevents progression of CKD to ESRD, so it is
reasonable to speculate that fewer patients with MetS will actually reach ESRD.
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METABOLIC SYNDROME AND RENAL REPLACEMENT THERAPY

Many patients receiving hemodialysis (HD) also have MetS. The mortality rate is very high in
the initial few months after HD initiation both in the United States[67] and worldwide[68]. A
significant proportion of this mortality is attributable to CVD, related to existing cardiovascular
comorbidities[69]. Therefore, patients with MetS starting chronic HD are at increased risk for
major cardiovascular events and mortality. The prevalence of MetS is quite high (often
exceeding 50%) in HD cohorts worldwide[70-72]. Interestingly, the presence of MetS has even
been extended to their relatives[73]. Longer-term follow-up also indicates a higher incidence of
cardiovascular events[74] and high rate of hospitalization[75]. Other co-morbid conditions may
co-exist with MetS in HD patients. A higher prevalence of moderate-to-severe periodontal
disease has been reported[76]. However, significant correlations were not noted in dialysis
patients with reduced bone mineral density[77], quality of life[78], or mood[78].
Several pathophysiological mechanisms may be operational during hemodialysis that could
further exacerbate the effects of MetS. Besides insulin resistance, hyperlipidemia, and
hypertension carried over from the pre-dialysis phase of CKD, further inflammation and
oxidative stress may result from dialysis treatment itself. There is a loss of antioxidants and
increase in leukocyte activation during dialysis[79-82]. This may occur through loss of vital
antioxidants through the hemodialysate, or reactions to semi-synthetic dialysis membranes, or
both. Dialysis patients are also prone to infections further promoting inflammatory stress.
Logistical difficulties in hemodialysis in obese patients, such as vascular access difficulties
leading to suboptimal renal functional replacement may promote inflammation. Chronic volume
expansion promotes worsening hypertension, further adding to morbidity. Insulin resistance,
even in those without diabetes, may also lead to chronic malnutrition as part of an overall
catabolic condition[83].
MetS has an impact on patients on peritoneal dialysis (PD) as well. When glucose-containing
solutions are used there is systemic glucose absorption via the peritoneal membrane, leading to
increased intra-abdominal fat[84] consistent with MetS. The increased glucose load increases
serum LDL cholesterol and triglyceride concentrations, which when combined with hypertension
and volume overload, may increase CVD[85]. MetS increases patient mortality on PD[86,87]
and also decreases PD technique survival in patients on PD for at least three months[87].
Technique failure and subsequent conversion to HD is also a stressful state that can cause
inflammation. MetS has been associated with an elevated white blood cell count and C-reactive
protein level, independently of infection but consistent with inflammation[88]. MetS is also
associated with lower circulating adiponectin levels in PD[89], and this may increase CVD risk.
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TREATING THE METABOLIC SYNDROME IN THE PRESENCE OF CKD

There is an obvious clinical need to reduce CKD morbidity and mortality, and MetS seems to be
an easily identified target for intervention. However, the approach is far from precise.
Randomized clinical trials in CKD patients are few and are limited by small sample sizes. Renal
outcomes are often not described as the primary outcomes. Studies of CKD prevention or
progression require large numbers of patients followed over long periods of time to gather
sufficient CVD or ESRD outcomes, and if MetS is added as an inclusion criterion, recruitment
difficulties are exacerbated. There is a shortage of high quality randomized, controlled trials in
nephrology generally[90]. Nonetheless, targeting MetS as a risk factor for CVD, for which CKD
patients are at risk is certainly reasonable.
An initial approach should include some combination among weight reduction, dietary
modification, and increased physical activity[91], preferably all three. A small clinical trial of 38
patients with MetS but without CKD, randomized to dietary weight loss, weight loss plus aerobic
exercise, or no treatment was able to demonstrate a relationship between weight loss,
albuminuria reduction, and improvement in eGFR, augmented by exercise[92]. An observational
analysis of PREMIER, a randomized trial of blood pressure lowering in obese subjects but again
without CKD, showed a relationship between reduction in waist circumference and urinary
albumin excretion[93]. A decrease in phosphate intake may be beneficial as well[93]. It is
unclear if these results indicate an improvement in incipient renal disease, or an improvement in
systemic endothelial dysfunction manifest as microalbuminuria. Achieving weight loss without a
corresponding loss in muscle mass may be difficult to achieve in CKD, especially ESRD. In a
sample of 2288 participants with CKD from the NHANES III survey, regular physical activity
but not diet was associated with decreased mortality[94]. Although unproven, it is likely that
patients with both CKD and MetS will especially benefit. A multi-disciplinary approach that
involves an exercise specialist to ensure regular physical activity and a dietician to achieve the
goal of weight loss through reduced calorie intake, while avoiding malnutrition at the same time
is preferable. Hospitalizations are likely to lead to setbacks. Smoking cessation has been
associated with reduced mortality in CKD[94]. Measurement of waist circumference or the
waist-to-hip ratio may allow for better compliance with existing MetS definitions[2-6] both for
diagnosis and follow-up.
Both pharmacotherapy and surgical procedures for weight loss in patients with MetS have been
explored. It is unclear if drugs prescribed for weight loss have significant adverse effects on
renal function. Orlistat may be beneficial for MetS in the general population[95]. Fibrates on the
other hand may worsen renal function[96], and could be harmful in patients with MetS and
CKD. Pharmacotherapy needs to be combined with lifestyle modification in order to have
significant effect, and would not be recommended in the absence of clinical trial data pertinent to
CKD. Bariatric surgery has been shown to improve MetS parameters and also decrease mortality
in the general population[97], and also reduce albuminuria[98]. However, the ability of CKD
patients to recover from major surgery needs to be considered. Clinical trials in CKD patients are
needed before this can be recommended.
Blood pressure control reduces CVD risk and CKD progression, and so relevant national
guidelines for blood pressure targets and therapeutic agents should be followed depending on the
presence or absence of CKD and/or diabetes, in the absence of specific guidelines for MetS
patients. Thiazides may worsen MetS, perhaps through hyperuricemia, hypokalemia, and
diabetes[99]. Renin-angiotensin system antagonists may prevent new-onset diabetes[100]. This
may be considered for those with MetS who have not yet developed diabetes. MetS is associated
with increased sympathetic activity, and so renal denervation has been considered when
hypertension is part of MetS[101]. However, the value of this procedure for achieving sustained
blood pressure reduction is controversial.
Management of dysglycemia requires special attention in the context of MetS. Metformin is
associated with improved insulin resistance and endothelial function[102]. However, metformin
is not used in more advanced CKD due to concerns surrounding lactic acidosis.
Thiazolidinediones may also be considered[103], but their side effect profile deserves special
attention. They may improve endothelial function as well as have anti-inflammatory
effects[103]. Weight loss may also help improve glycemic control, but dietary conflicts among
diabetes-related restrictions (such as carbohydrates) and CKD-related restrictions (potassium and
phosphorus) may be especially problematic in MetS where total caloric intake must also be
reduced and protein intake maintained. Specialized dietician input is again required.
Finally, the use of statins in MetS requires consideration. Statins may reduce proteinuria[104],
either through improved endothelial function or reduction in systemic inflammation[104,105].
Success with statins in reducing cardiovascular events in ESRD[106] has been variable.
A summary of possible therapeutic interventions for MetS in the context of CKD is provided in
Table Table4.4. In the absence of firm data, relevant national guidelines should be followed for
each individual cardiovascular or CKD-related risk factor.
Table 4
Possible clinical interventions for metabolic syndrome in chronic kidney diseasea,b
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CONCLUSION
At this point, it remains unclear whether MetS adds further cardiovascular risk to that conferred
by CKD alone. Further research is first required to firmly establish the link between MetS and
incidence of CKD in the first instance, and then between MetS and the progression of CKD. A
single large, prospective clinical trial in human subjects that addresses both CKD incidence and
progression in established CKD will help to provide the necessary justification for MetS
intervention. However, the major clinical concern surrounding MetS is its association with CVD.
A prospective clinical trial of intervention targeted to multiple MetS parameters in CKD would
help address whether MetS is more than the sum of its parts in the context of CKD. Until then,
we are left with using surrogate markers such as proteinuria or microalbuminuria for both CKD
and CVD. Statins, fibrates, and renin-angiotensin system antagonists allow for targeting specific
MetS components including diabetes, hyperlipidemia, hypertension, and microalbuminuria. In
combination with aggressive lifestyle modification, there is potential in the meantime for
reducing MetS, CKD, and CVD mortality. Beneficial snapshot effects may be found in the
literature for a particular intervention in one CKD sub-population and not another, such as in the
case of statins. However, viewing CKD as a longitudinal construct allows for better
understanding of the pathophysiology of CVD and CKD progression with MetS, and may thus
allow for more rational therapeutic choices.
Definition of Metabolic Syndrome

We included studies that used the following definitions of metabolic syndrome: NCEP-ATP III
criteria (2,16), modified NCEP-ATP III criteria (3,17), IDF definition (3), or WHO criteria (4,5)
(see Supplementary Table 1).
Search Strategy and Data Extraction

MEDLINE (1966 to October 2010), SCOPUS (October 2010), and Web of Science were
searched using optimally sensitive search strategies for relevant studies (see Supplementary
Search Strategy). We also reviewed reference lists of all included studies for any additional
relevant studies. Two reviewers (G.T. and S.D.N.) independently reviewed the search results and
extracted from included studies relevant data regarding study design and setting (such as country
of origin, years of study, and follow-up duration), participant characteristics (age, gender, and
race), and outcome measures (described below) using a standardized data extraction form. The
authors of the included studies were contacted for additional details regarding their studies.
Disagreements were resolved in consultation with an arbitrator (T.R.S.).
Study Quality
Study quality was assessed according to previously published guidelines (18,19). We assessed
the risk of bias among the included studies on the basis of the following six domains: (1) study
participation, (2) study attrition, (3) prognostic factor measurement, (4) outcome measurement,
(5) confounding measurement, and (6) statistical analysis. Each of these individual domains was
rated as Yes, Partly, No, or Unclear. The individual quality domain was categorized as
low risk for bias (Yes) when adequate data were reported to assess the study quality and the
study met the criteria for that quality domain, intermediate risk (Partly) when the study reported
incomplete data to assess that quality domain, and high risk (No) when the study reported
adequate data but did not meet the criteria for that quality domain. Studies that did not report
data to assess the quality were categorized as Unclear and thus potentially at high risk for bias.
We also reported the individual confounding factors that were adjusted in the multivariate
analyses of the included studies.
Outcome Measures
The following outcome measures were considered for inclusion: (1) development of eGFR <60
ml/min per 1.73 m2 using the Modified Diet in Renal Disease equation or CockcroftGault
equation or creatinine clearance <60 ml/min per 1.73 m2 using 24-hour urinary studies and (2)
development of microalbuminuria defined as urinary albumin-to-creatinine ratio (UACR) of 30
to 300 mg/g or 24-hour urine albumin excretion of 30 to 300 mg, and overt proteinuria defined
as UACR >300 mg/g or 24-hour urine protein excretion >300 mg.
Statistical Analyses
For dichotomous outcome measures such as the development of eGFR <60 ml/min per 1.73 m2,
we pooled only the risk estimates (hazard ratio or relative risk [RR] or odds ratio [OR]) from
individual cohort studies. Only the most adjusted risk estimates that were reported in the studies
were extracted and included in the analysis. The data were pooled, and the OR were reported
using the random effects model because of anticipated statistical heterogeneity, but the fixed
effects model was also used to ensure robustness of the model chosen and susceptibility to
outliers. Heterogeneity was analyzed using a chi-squared test on N-1 degrees of freedom, with an
alpha of 0.05 used for statistical significance and with the I2 test (20).
Subgroup analysis and univariate random-effects metaregression were conducted to explore
possible sources of heterogeneity including participant-specific characteristics such as age,
gender, and race of study participants and study-specific characteristics such as duration of
follow-up, sample size, and the definitions used. However, because of the lack of a sufficient
number of studies providing relevant details, we conducted subgroup analysis on the basis of the
definition of MetS, study duration, and study population alone. Univariate metaregression
included age of study participants, number of participants, duration of follow-up, and year of
study publication. Separate analyses for the development of eGFR <60 ml/min per 1.73 m2 and
microalbuminuria or proteinuria were planned. We also examined the influence of each study by
eliminating individual studies and assessing the effect on the cumulative risk estimate. The
CochraneArmitage trend test was used to test the trend for dose-response relationship. We
investigated the presence of publication bias graphically and used Egger's regression test and its
implications with the fail-safe n and the trim and fill method. Analyses were performed using
Comprehensive Meta-analysis (Biostat, Englewood, NJ) and STATA/SE 10.1 (Stata
Corporation, College Station, TX).
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Results
Search Results
We identified 5579 citations with the combined search of the MEDLINE, SCOPUS, and Web of
Science databases (Figure 1). We excluded 5538 studies after title and abstract review. Forty-one
studies were reviewed in detail (full text), and 11 studies (n = 30,146) that met our inclusion
criteria were included in the meta-analysis (1014,2126).
Figure 1.
Study flow diagram: included studies and reasons for exclusion of studies.
Study Characteristics
Table 1 summarizes the various characteristics of included studies. The sample size of included
studies ranged from 176 to 17039 patients with MetS. Three studies included United States or
European populations (1012), whereas eight studies included Asian populations (13,14,2126).
Follow-up duration ranged from 3.5 to 12 years. Nine studies excluded participants with diabetes
(1012,14,2226). Five studies used the modified NCEP-ATP III criteria for diagnosis of MetS
(14,21,22,25,26); three studies used the NCEP-ATP III criteria (10,12,23); two studies examined
both the modified NCEP-ATP III and IDF definitions (11,24); and one study classified patients
as having MetS on the basis of modified NCEP-ATP III, NCEP-ATP III, and IDF definitions
(13). For studies in Asian populations that reported more than one definition, we selected
outcomes using the modified NCEP-ATP III criteria for this analysis. Three studies used body
mass index (BMI) 25 kg/m2 instead of waist circumference to assess obesity (14,25,26) because
of a lack of data. Only four studies reported the use of creatinine calibration (10,13,14,25).
Table 1.
Characteristics of prospective cohort studies that reported the development of chronic kidney disease
(eGFR <60 ml/min per 1.73 m2 or CrCl <60 ml/min per 1.73 m2) and/or proteinuria in patients with
metabolic syndrome
Ten studies reported MetS and the outcome of development of eGFR <60 ml/min per 1.73 m2, of
which three studies also reported the outcome of microalbuminuria or proteinuria separately
(12,14,26). One study reported MetS and the outcome of proteinuria alone (11). Sun et al. (24)
reported CKD defined as eGFR <60 ml/min per 1.73 m2 or proteinuria but did not report these
separately. For our review, we included this study in the analysis of development of eGFR <60
ml/min per 1.73 m2.
Study Quality
Study quality varied among the included studies, and the study quality for each individual
domain is detailed in Table 2. Most studies were at low risk for bias for study participation and
prognostic factor assessment. The included studies had different risk profiles (high risk,
intermediate risk, or unclear risk) for other domains such as study attrition, outcome assessment,
confounding, and study analysis.
Table 2.
Quality assessment of the prospective cohort studies included in the systematic review
Metabolic Syndrome and Development of eGFR <60 ml/min per 1.73 m 2

Ten cohort studies reported risk estimates for the development of eGFR <60 ml/min per 1.73
m2 in patients with MetS. In the pooled analysis, MetS was associated with the development of
eGFR <60 ml/min per 1.73 m2 (OR, 1.55; 95% confidence interval [CI], 1.34, 1.80) (Figure 2).
We further examined the associations of individual components of MetS and the risk for eGFR
<60 ml/min per 1.73 m2. All individual components of MetS showed a positive association with
the development of eGFR <60 ml/min per 1.73 m2 (Table 3). The strength of association between
MetS and the development of eGFR <60 ml/min per 1.73 m2 seems to increase as the number of
components increased from 1 to 5 (trend P-value 0.02). Although patients with one component
had no significant increase in the odds for development of eGFR <60 ml/min per 1.73 m2,
patients with all five components of MetS had an OR of 1.96 (95% CI 1.71, 2.24) for
development of eGFR <60 ml/min per 1.73 m2 (Table 4).
Figure 2.
Metabolic syndrome and risk for development of estimated GFR <60 ml/min per 1.73 m2.
Table 3.
Individual components of metabolic syndrome and their risk for development of eGFR <60 ml/min per
1.73 m2
Table 4.
Number of components of metabolic syndrome and its associations with development of eGFR <60
ml/min per 1.73 m2
Exploration of Heterogeneity
There was significant statistical heterogeneity between the included studies (I2 = 80%) in the
pooled analysis of MetS and development of eGFR <60 ml/min per 1.73 m2. The risk estimates
and the heterogeneity did not differ when individual studies were removed one at a time.
Therefore, we conducted subgroup analyses and univariate metaregression. There was no
difference in the risk estimates between the studies that used the NCEP ATP-III criteria and the
modified NCEP ATP-III criteria. Similarly, there were no differences among studies that had
follow-up for 5 years versus <5 years and studies conducted in the United States and
Europe versus Asian countries (see Supplementary Table 2). When examined as a continuous
measure, age of study participants, number of participants, duration of follow-up, and year of
study publication did not seem to explain the heterogeneity.
Metabolic Syndrome and Development of Microalbuminuria or Proteinuria

We did not pool the results of individual studies because proteinuric outcomes were not
consistently reported. After adjusting for demographics, education, and smoking status,
Lucove et al. (12) reported an increased hazard (hazard ratio, 1.26; 95% CI, 0.99, 1.60) for the
development of UACR >30 mg/g among American Indians with MetS. Tozawa et al. (14)
reported a two-fold increased risk for developing dipstick-positive proteinuria (RR, 2.09; 95%
CI, 1.55, 2.81) in a Japanese population with MetS. In another Japanese cohort with MetS,
Watanabe et al. (26) reported a 76% (95% CI, 1.57, 1.98) increased risk for developing 1+
dipstick proteinuria. Bonnet et al. (11) reported a higher risk for proteinuria only in men with
MetS (RR, 1.87; 95% CI, 1.25, 2.81) using the IDF definition in a French cohort.
The Metabolic Syndrome and Risk of Chronic Kidney Disease:

Pathophysiology and Intervention Strategies
Heather A. LaGuardia,1 L. Lee Hamm,1 and Jing Chen2
1
Tulane University, New Orleans, LA 70112, USA
2
Tulane School of Medicine, Tulane University 1430 Tulane Avenue, SL-45, New
Orleans, LA 70112, USA
Received 16 June 2011; Revised 14 December 2011; Accepted 14 December 2011
Academic Editor: Andra Name Colado Simo
Copyright 2012 Heather A. LaGuardia et al. This is an open access article distributed
under the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Metabolic syndrome is characterized by a clustering of cardiovascular risk factors,
including abdominal obesity, elevated blood pressure and glucose concentrations, and
dyslipidemia. The presence of this clinical entity is becoming more pervasive throughout
the globe as the prevalence of obesity increases worldwide. Moreover, there is increased
recognition of the complications and mortality related to this syndrome. This paper looks
to examine the link between metabolic syndrome and the development of chronic kidney
disease.
1. Introduction
Metabolic syndrome refers to a cluster of metabolic abnormalities (abdominal obesity,
hyperglycemia, dyslipidemia, and hypertension) related to a state of insulin resistance,
often associated with an overweight or obese state. This clinical entity has been known to
increase the risk of cardiovascular disease (CVD), type 2 diabetes, chronic kidney disease
(CKD), and total mortality.
Metabolic syndrome is highly prevalent worldwide, with a prevalence ranging from 10 to
40% in different populations [13]. Recently emerging data have suggested that metabolic
syndrome is an important risk factor for CKD. CKD is a major risk factor for CVD and
premature death [47]. Better understanding of the underlying pathophysiology of
metabolic syndrome related to CKD will help to identify potential treatment strategies to
reduce CKD risk. The purpose of this paper is to explore the potential pathophysiology and
treatment strategies related to metabolic syndrome and CKD by integrating available data
from the literature.
2. Definition of Metabolic Syndrome

In 1923, Kylin [8] first described a constellation of metabolic disturbances that included
hypertension, hyperglycemia, and hyperuricemia. Later scientists noted that, when these
syndromes clustered together, they could have disastrous health consequences and referred
to the clustering as syndrome X, insulin resistance syndrome, the deadly quartet, and
obesity dyslipidemia syndrome [913]. Between 1998 and 2005, three definitions of
metabolic syndrome had been developed and widely used (Table 1). The three definitions
stated that the primary components of the syndrome included central obesity, dyslipidemia,
elevated blood pressure, and increased glucose. Furthermore, previous studies have
reported that all three definitions will identify persons at increased risk for diabetes,
cardiovascular disease, and all-cause mortality [3, 1416]. However, it is noteworthy that
the NCEP ATP III definition was a more powerful predictor of CVD and diabetes than the
IDF definition [1720], while the IDF definition identified more patients than the NCEP
ATP III definition [19, 21] according to recent studies. Therefore, NCEP ATP III definition
may have had more clinical impact. In 2009, a global definition was developed by multiple
organizations including the International Diabetes Federation (IDF), National Heart, Lung,
and Blood Institute (NHLBI), the World Heart Federation, the International
Atherosclerosis Society, and the American Heart Association (AHA) in an effort to
harmonize clinical diagnosis of metabolic syndrome. Their definition, summarized in
Table 2, is the same as that by NCEP ATP III with an exception that the criteria for elevated
waist circumference are based on population- and country- specific definitions [22].
Table 1
Table 2
3. Metabolic Syndrome and Risk of Chronic Kidney Disease

In the Last ten years, new research has examined the link between kidney disease and
metabolic syndrome. In 2004, Chen et al. [23] showed that metabolic syndrome was an
independent risk factor of CKD. They examined the association of metabolic syndrome
and risk of CKD in over 6000 subjects who participated in the Third National Health and
Nutrition Examination Survey (NHANES III) and documented that metabolic syndrome
was independently associated with risk of CKD. In 2005, Kurella et al. [24] went further
to include all metabolic syndrome traits in relation to risk for CKD. Using data from the
ARIC study, a prospective longitudinal study of CV disease risk factors in 10,096 middle-
aged nondiabetic adults, they found that over a nine-year time span metabolic syndrome
increased the risk of developing chronic kidney disease by approximately 50%. The
multivariable-adjusted odds ratio of developing CKD in those with metabolic syndrome
was 1.43 (95% CI 1.181.73). They also looked at the individual traits associated with the
syndrome and found that compared with an adult who has no metabolic syndrome traits,
risk for CKD in someone with all five of the traits is two and a half times higher. In 2006,
Ninomiya et al. examined the relationship between metabolic syndrome and CKD [25].
They performed a slope analysis of the association between the glomerular filtration rate
(GFR) slope and metabolic syndrome by using a multiple regression model. GFR
decreased significantly faster in patients with 4 or more metabolic syndrome components
compared with those who had 1 or no components. In 2007, Tozawa et al. [26] conducted
a prospective study to examine metabolic syndrome as a risk factor for CKD in an Asian
population. They examined CKD in 6,371 subjects without CKD or diabetes mellitus at
baseline from 1997 through 2002 in Okinawa, Japan. During the 5-year followup, 369
(5.7%) participants developed CKD. After adjusting for age, sex, current cigarette
smoking, and alcohol drinking habits at baseline, the relative risk of developing CKD was
1.86 (95% confidence interval: 1.432.41, < 0 . 0 0 0 1) in subjects with metabolic
syndrome.
4. Pathophysiology of Metabolic Syndrome which Predisposes to CKD

4.1. Insulin Resistance
Insulin resistance has been considered an important pathophysiological factor for
metabolic syndrome [27]. Insulin resistance has traditionally been defined by defective
insulin action resulting in fasting hyperinsulinemia. Yet, even before fasting
hyperinsulinemia develops, postprandial hyperinsulinemia exists. The resultant
hyperinsulinemia stimulates glucose uptake by muscle and suppresses endogenous glucose
production in the liver. In insulin-resistant conditions, the ability of insulin to augment
glucose uptake and inhibit hepatic glucose production is impaired. This creates a state of
hyperglycemia that stimulates beta cells to secrete large amounts of insulin postprandially.
High insulin concentration may overstimulate the cells of the arterial wall in the skeletal
muscle.
Binding of insulin to the insulin receptor normally leads to activation of its tyrosine kinase
activity and autophosphorylation of specific tyrosine residues of the receptor. The activated
insulin receptor phosphorylates tyrosine residues on substrate proteins initiating a signaling
cascade. The two major pathways for insulin signaling are the phosphatidylinositol-3
kinase (PI-3K) and the mitogen-activated protein (MAP) kinase pathways [28]. The PI-3K
pathway is initiated by tyrosine phosphorylation of a member of the insulin receptor
substrate family, which is associated with the p85 regulatory subunit leading to activation
of the enzyme. PI-3K causes phosphatidylinositol 3,4,5-phosphate (PIP3) to be produced.
This results in activation of Akt and downstream effector molecules that mediate metabolic
response to insulin. This includes translocation of the glucose transporter type 4 (GLUT4)
into the membrane. The MAP kinase pathway begins with phosphorylation of insulin
receptor substrate, which binds Grb2 and activates Ras. Ras then binds and disinhibits Raf,
which activates MEK1 kinase. MEK1 activates extracellular signal-regulated kinases
ERK1 and ERK2. The ERKs mediate the mitogenic and proinflammatory responses of
insulin signaling. In metabolic syndrome and type 2 diabetes, the pathways leading to
activation of PI-3K are blocked, possibly through serine phosphorylation of the insulin
receptor, leaving the MAP kinase pathway open. The activation of ERK MAPK pathway
stimulates smooth muscle cell growth and proliferation, which maintains normal sensitivity
to insulin even in insulin-resistant conditions. The overall effect may be to enhance
atherogenesis.
Another key feature of metabolic syndrome is that free fatty acid production and release
from adipocytes are not suppressed normally with the usual levels of insulin. Adipocyte
resistance to the antilipolytic effect of insulin and the consequent elevated plasma free fatty
acid levels may play an important role in the development of insulin resistance in muscle
and other target tissues. Furthermore, excess fatty acid blocks the PI-3K signaling pathway.
Impairment in the PI-3K pathway could contribute to vascular endothelial dysfunction due
to decreased nitric oxide [2729].
Kubo et al. examined the effect of hyperinsulinemia on renal function in a general Japanese
population [30]. The study examined 2446 residents of a town in Japan age 4079 without
renal failure and had them undergo a series of physical and laboratory analyses including
glucose tolerance test. The results were interpreted through correlation analysis and
showed serum insulin, blood pressure, total cholesterol, low-density lipoprotein
cholesterol, triglycerides, and body mass index were all negatively correlated with the
reciprocal of serum creatinine level. In multiple regression analysis, the correlation
between the sum of insulin levels and the reciprocal of serum creatinine remained
significant even after controlling for age, sex, body mass index, blood pressure, total
cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol,
triglycerides, alcohol intake, and smoking habits. This study suggested that
hyperinsulinemia was a significant relevant factor of renal function in the general
population. Renal dysfunction from insulin resistance and hyperglycemia is thought to be
associated with the activation of the renin-angiotensin system (RAS) leading to elevated
angiotensin II and aldosterone levels. The elevation affects the insulin/insulin-like growth
factor-1 signaling pathways, causing oxidative stress leading to endothelial disruption, and
even the development of CVD [31]. Insulin resistance and hyperinsulinemia are associated
with decreased endothelial production of nitric oxide and increased oxidative stress which
have been also implicated in the progression of diabetic nephropathy [32].
4.2. Obesity and Waist Circumference
Visceral adipose tissue is the abdominal fat of the mesentery and omentum. When free
fatty acids are released from the visceral fat, they drain into the portal circulation. It has
been postulated that increases in this type of fat are directly associated with increases in
risk for the sequel of metabolic syndrome [33]. In addition, increases in abdominal
subcutaneous fat would release lipolysis products into the systemic circulation and avoid
direct effects on hepatic metabolism (i.e., glucose production, lipid synthesis, and secretion
of prothrombotic proteins such as fibrinogen and plasminogen activator inhibitor 1) [34].
Furthermore, human adipocytes produce an as yet unidentified mineralocorticoid-releasing
factor that stimulates adrenal aldosterone production by means of paracrine or endocrine
mechanisms [35, 36]. Elevated levels of aldosterone promote insulin resistance and
hypertension and therefore the development of the metabolic syndrome [37].
When biopsies of obese patients are examined, focal and segmental glomerulosclerosis and
glomerulomegaly are the most common morphological renal lesions [38]. Early changes
noted upon review of biopsies seen in nondiabetic patients with only mild metabolic
abnormalities and mild hypertension include increased glomerular cell proliferation,
increased mesangial matrix, thicker basement membrane, and increased expression of
glomerular transforming growth factor-beta [39]. The mechanisms of obesity-induced
renal injury likely result from a combination of hemodynamic and metabolic abnormalities.
Many factors contribute to the increase in both glomerular filtration rate (GFR) and rise in
renal plasma flow (RPF) observed in obese patients. Insulin resistance likely causes an
increase in the efferent arteriolar pressure due to decrease of noradrenaline-induced
efferent arteriolar constriction by insulin. Therefore, the transcapillary pressure gradient
increases resulting in hyperfiltration [40]. Insulin also stimulates the synthesis of IGF-1
and IGF-2, both promoting glomerular hypertrophy [38]. In 2011, Mathew et al. proposed
that circulating cytokines (leptin, adiponectin) and inflammatory markers produced by
adipose tissue are directly affecting cells in the renal glomeruli [28]. Moreover, elevated
aldosterone in obesity promotes fibrosis and target-organ dysfunction by stimulating
plasminogen activator inhibitor, transforming growth factor 1, and reactive oxygen
species (ROS) [4143]. Aldosterone also promotes loss of glomerular podocytes and a
consequent decrease in the slit-pore membrane integrity, with consequent proteinuria [44
47]. In addition, aldosterone increases renal tubular and interstitial oxidative stress and
inflammation, processes that promote salt-induced tubuloglomerular injury, by means of
rapid nongenomic effects [28].
4.3. Dyslipidemia
This condition is characterized by an increase in elevated triglycerides (and increased
VLDL particle number), increased small LDL particles, and low HDL cholesterol.
Increased numbers of VLDL and LDL particles lead to an increased level of total apo-B
usually observed with atherogenic dyslipidemia. Additionally, small triglyceride-rich
lipoproteins have also been found to be atherogenic [48]. The LDL particles associated
with the metabolic syndrome and atherogenic dyslipidemia tend to be small and dense.
Smaller LDLs have been postulated to penetrate more easily into the arterial wall as well
as be more prone to atherogenic modification [49]. Low HDL is a risk predictor for the
atherogenic process.
Dyslipidemia seen in metabolic syndrome is postulated to cause CKD by inflammation and
increased oxidative stress, which would cause endothelial damage and atherosclerosis
diseases [5052]. Manttari et al. used meta-analysis to postulate that elevated triglycerides
and low HDL cholesterol in the plasma are independent risk factors for the development
of chronic kidney disease [53]. Additionally, Muntner et al. [54] noted in the ARIC study
that high triglycerides and low HDL cholesterol in plasma significantly increased the
probability of developing renal dysfunction. It has even been examined that use of statins
may slow the progression of chronic kidney disease [55].
4.4. Elevated Blood Pressure
Obese persons have a higher prevalence of elevated blood pressure than lean persons.
Moreover, a higher blood pressure is a strong risk factor for cardiovascular disease [56].
Well-known complications of hypertension are CHD, stroke, left ventricular hypertrophy,
heart failure, and chronic renal failure. The relation between insulin resistance and
hypertension is well established [57]. Insulin is a vasodilator when given intravenously to
people who are not obese [58]. In the setting of insulin resistance, the vasodilatory effect
of insulin can be lost [59], but the renal effect on sodium reabsorption preserved. Metabolic
syndrome is also implicated in salt-sensitive hypertension. The enhanced insulin resistance
in CKD may increase sodium reabsorption by hyperinsulinemia. This results in sodium
retention and salt-sensitive hypertension. In addition, Fujita [60] noted that, in obese rats,
adipocyte-derived aldosterone releasing factors lead to hyperaldosteronism.
Hyperaldosteronism results in salt-sensitive hypertension as well as proteinuria in the
obese hypertensive rats. Salt loading exacerbated the proteinuria and also resulted in
cardiac diastolic dysfunction. Fujita proposed that salt and aldosterone worked in synergy
with the cardiovascular system through overproduction of oxidative stress. ROS, induced
by adipokines such as tumor necrosis factor-alpha, nonesterified fatty acids,
angiotensinogen activated the mineralocorticoid receptor, in an aldosterone-independent
fashion. The hypothesis proposed aldosterone and mineralocorticoid receptor activation
may play an important role in the development of salt-sensitive hypertension, as well as
the cardiovascular and renal injury seen in metabolic syndrome. Fatty acids themselves can
mediate relative vasoconstriction [61].
5. Interventions
5.1. Diet
Some experts debate the clinical utility of aggregating individual risk factors into a specific
diagnosis of metabolic syndrome when medically each risk factor is addressed separately.
At this time, there is no single metabolic syndrome diet recommended. The main strategy
has been to reverse contributory factors such as an atherogenic diet, obesity, and a
sedentary lifestyle [62]. Weight management and physical activity are recommended as
first-line therapy in order to delay the progression of symptoms [63]. Epidemiological
evidence suggests a lower prevalence of metabolic syndrome with dietary patterns that are
rich in fruits, vegetables, whole grains, dairy products, and unsaturated fats. Research from
the dietary approaches to stop hypertension (DASH) intervention studies demonstrates
beneficial effects of an eating plan rich in low-fat dairy foods, fruits, and vegetables on
blood pressure and lipids. A reduced calorie DASH diet compared to a control and weight
loss diet reduced most of the metabolic syndrome risks in both men and women and
improved some components beyond that seen in a weight loss diet [64]. The DASH diet
which is rich in calcium, magnesium, and potassium may also lower the risk of stroke and
hypertension. Fiber and other phytonutrients in fruit and vegetables may be protective by
lowering cholesterol or markers of inflammation. Some studies [65, 66] suggest an inverse
association between dairy consumption and risk for metabolic syndrome. In young
overweight adults, the incidence of metabolic syndrome were lower by more than two-
thirds among individuals in the highest category of dairy intake (>5 servings per day)
compared to lowest category (<1.5 servings a day) [67]. In addition, a dietary pattern that
had higher intake of low-fat dairy has been associated with a lower risk of type 2 diabetes
in middle aged or older women and with a 9% lower risk for type 2 diabetes in men [65].
Giugliano et al. explored possible mechanisms underlying a dietary intervention and
randomly assigned 180 patients (99 men and 81 women) with the metabolic syndrome to
either a Mediterranean-style diet (an increase in daily consumption of whole grains,
vegetables, fruit, nuts, and olive oil) or a cardiac diet with a decreased fat intake composed
of less than thirty percent of total calories. Only forty patients in the intervention group
still had metabolic syndrome after two years compared with seventy-eight patients who
consumed the control diet [68].
Given the increased blood pressure reactivity to dietary salt in patients with metabolic
syndrome, a reduction in dietary salt may have a beneficial effect on lowering systolic
blood pressure as suggested by Hoffmans study (8.2g/day to 2.3g/day of salt) [69].
Recently, Chen et al. reported that metabolic syndrome may enhance blood pressure
response to sodium intake in nondiabetics [70]. However, if low-sodium diet could lead
reduction of metabolic syndrome-related morbidity and mortality remains to be
investigated in clinical trials.
5.2. Oral Hypoglycemic Agents
In the Diabetes Prevention Program trial, metformin reduced the risk of diabetes and the
metabolic syndrome in individuals with impaired fasting glucose and impaired glucose
tolerance [71]. The study examined 3234 nondiabetic persons with elevated fasting and
postload plasma glucose concentrations. Then assigned participants to metformin (850mg
twice daily) or a lifestyle-modification program and followed them for 2.8 years. The
lifestyle intervention reduced the incidence by 58% (95% CI, 48%66%) and metformin
by 31% (95% C, 17%43%), as compared with placebo; the lifestyle intervention was
significantly more effective than metformin. In a 10-year followup of this study, it was
found that prevention or delay of diabetes with lifestyle intervention or metformin could
persist for at least 10 years [72]. In patients with the metabolic syndrome but normal
glucose tolerance, metformin has been shown to improve endothelial function [73].
Unfortunately, metformin is contraindicated in patients with chronic kidney disease with
reduced GFR. This is due to the fact that renal clearance of metformin and lactate is
reduced, leading to increased levels of both and possibly causing lactic acidosis due to a
buildup of lactic acid [74].
Thiazolidinediones have also been associated with protection effects. In the DREAM
study, rosiglitazone reduced the three-year incidence of type 2 diabetes by 60 percent in
patients with impaired glucose tolerance or impaired fasting glucose who were taking the
medication at the time of testing [75]. The management of insulin resistance with
thiazolidinediones (TZDs) has resulted in greater attention to activators of the peroxisome
proliferator-activated receptors (PPARs). TZDs exert much of their effect on insulin
resistance via activation of PPAR-gamma. TZDs not only improve glucose control but
favorably affect both free fatty acid metabolism and insulin action. Szapary et al. examined
the effect of pioglitazone in patients with the metabolic syndrome and demonstrated a
significant increase in HDL-C and favorable effects on lipid subfractions without an effect
on triglycerides or low-density lipoprotein cholesterol (LDL-C) concentrations [76]. Tan
et al. [77] noted that pioglitazone therapy resulted in greater improvements in the
atherogenic index of plasma and lowered triglyceride levels effectively while achieving
greater increases in HDL-C when compared with rosiglitazone.
5.3. Lipid-Lowering Agents
The efficacy of statins in making marked reductions in LDL cholesterol, modest reductions
in TG, and small increases in HDL cholesterol is well documented. ATP III recommended
a goal serum LDL cholesterol of less than 100mg/dL (2.6mmol/L) for secondary
prevention in patients with type 2 diabetes [78, 79]. For this reason the use in patient with
metabolic syndrome has been examined. Patients in the 4S trial who met the lipid criteria
for the metabolic syndrome were treated with simvastatin, 20 or 40mg/d. It was noted that
they had a 37.5% versus a 36.0% decrease, respectively, in LDL cholesterol, a 24.1%
versus 6.7% decrease in TG, and a 10.3% versus a 0.6% increase in HDL cholesterol [80].
Rosuvastatin, 10mg/d administered to patients with the metabolic syndrome, reduced LDL
cholesterol by 47%, apolipoprotein B by 37%, and TG by 23%, while increasing HDL
cholesterol by 10% [81]. Multiple statins have been shown to reduce cardiovascular events
in patients with and without CVD, suggesting that this is a class effect of these drugs. Some
of the CVD risk reduction produced by statins may be attributable to nonlipid pleiotrophic
effects of these drugs [82]. Treatment of patients with known coronary disease and the
metabolic syndrome with atorvastatin 80mg, compared to atorvastatin 10mg, decreased
the rate of major cardiovascular events at five years (9.5 versus 13 percent, HR 0.71, 95%
CI 0.610.84) [79].
In 2009, Robinson et al. [83] evaluated the lipid-lowering efficacy of ezetimibe/simvastatin
10/20mg versus atorvastatin 10 or 20mg, and ezetimibe/simvastatin 10/40mg versus
atorvastatin 40mg in 1,128 patients with hypercholesterolemia and the metabolic
syndrome. They noted that greater improvements in the levels of LDL cholesterol, non-
high-density lipoprotein cholesterol, apolipoprotein B, and lipid/lipoprotein ratios resulted
with ezetimibe/simvastatin compared with atorvastatin at all specified dose comparisons
( < 0 . 0 0 1).
5.4. Antihypertensive Therapy
Patients with hypertension and the metabolic syndrome have high risk of suffering from
future cardiovascular and kidney disease. At present there are no large-scale, randomized
trials to establish the antihypertensive drug of choice for patients with metabolic syndrome.
Most investigators have considered angiotensin-converting enzyme inhibitors (ACEI) as
superior to beta-blockers and thiazide diuretics [84]. The adverse potential metabolic side
effects of thiazides and beta-blockers on increase of blood lipids and glucose have led to
favoring of ACEI and calcium channel blockers (CCB) [85]. Beta-blockers also promote
weight gain, and both thiazides and beta-blockers are associated with an increased
incidence of diabetes, compared to CCB and ACEI [86].
Wright et al. [87] conducted subgroup analysis of the ALLHAT study reporting that
findings fail to support the preference for CCBs, alpha-blockers, or ACEIs compared with
thiazide-type diuretics in patients with the metabolic syndrome. Wright examined the
metabolic and cardiovascular outcomes of the ALLHAT trial in patients stratified
according to race (black versus nonblack) and the presence or absence of the metabolic
syndrome. Among all the patients studied, chlorthalidone had the least favorable effects on
blood glucose and cholesterol levels than lisinopril, amlodipine. In patients without the
metabolic syndrome, both the ACEI and the CCB lowered the incidence of type 2 diabetes
significantly, compared to the thiazide [88]. Wright also noted that black patients with the
metabolic syndrome had worse outcomes with lisinopril, compared to chlorthalidone, with
respect to every outcome measured, likely resulting from a 35 mmHg higher systolic
pressure in the black patients on lisinopril, compared to those on chlorthalidone. Wright
concluded that ACEI should not be the first-line monotherapy for black patients with the
metabolic syndrome [87].
5.5. Resistance Training
Over the last decade, physicians have been examining the effects of resistance training on
metabolic syndrome. Reduced muscle mass as a result of normal aging and decreased
physical activity have been postulated behind the high prevalence of this disorder.
Improved glycemic control, improved blood lipid profiles, and decreased BP are important
for reducing microvascular and macrovascular complications in people with metabolic
risk. As with increasing adiposity in aging and loss of muscle mass, the insulin-mediated
glucose uptake and TG disposal in the skeletal muscle of elderly persons is reduced and
the maintenance of a large muscle mass can contribute to the prevention of type 2 diabetes,
which is associated with cardiovascular disease. Resistance training is contributing to the
decrease of major risk factors for the metabolic syndrome and should be recommended for
the management of type 2 diabetes. Although the number of studies on the effects of
resistance training on blood pressure is small, Strasser conducted meta-analysis confirming
that resistance training does not increase blood pressure as was once thought and may even
have potential benefits on resting systolic blood pressure [89].
5.6. Surgery
In the prospective controlled clinical study conducted by Lee et al., metabolic syndrome
was prevalent in 52.2% of morbidly obese individual enrolled. Significant weight reduction
1 year after surgery markedly improved all aspects of the metabolic syndrome and resulted
in a cure rate of 95.6% [90]. Obesity surgery performed by laparoscopic surgery is
recommended for obese patients with the metabolic syndrome that have not responded to
conservative measures.
6. Conclusion
Compelling data have indicated that metabolic syndrome increases the risk of CKD.
Experimental studies have suggested that metabolic syndrome may induce CKD via
multiple mechanic pathways. While we are waiting for randomized clinical trial and even
new drug development in treating metabolic syndrome to reduce risk of CKD, current key
strategies should include prevention and treatment of obesity and insulin resistance.
Lifestyle modification particularly including low sodium diet and increasing physical
activity would be important approaches. Aldosterone antagonists would also be particular
of interest to test in clinical trial in treating metabolic syndrome to reduce CKD risk. At
the present, early identification of metabolic syndrome and treatment of individual
components of metabolic syndrome may reduce the risk of CKD. However, these
approaches need be further tested in large randomized clinical trial to verify their effect on
reducing CKD risk

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