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189]

Saudi J Kidney Dis Transpl 2015;26(5):931-940

2015 Saudi Center for Organ Transplantation Saudi Journal
of Kidney Diseases
and Transplantation

Original Article

Metabolic Syndrome and Chronic Kidney Disease

Anis Belarbia, Safa Nouira, Wissal Sahtout, Yosra Guedri, Abdellatif Achour

Department of Nephrology, Dialysis and Transplantation, Sahlouls University Hospital,

Sousse, Tunisia

ABSTRACT. To determine the prevalence of metabolic syndrome (MS) in chronic kidney

disease (CKD) patients as well as its effects on the progression of CKD, we conducted a
prospective, longitudinal study including 180 patients with chronic renal failure followed at the
outpatient service of Nephrology at the Salouls University Hospital of Sousse (Tunisia) over six
months. Our study population consisted of 101 men and 79 women. Chronic glomerulonephritis
(36.6%) was the most frequent nephropathy. The mean serum creatinine was 249 200 mmol/L
and the mean estimated glomerular filtration rate (eGFR) was 55.8 49.2 mL/min. Cardio-
vascular (CV) impairment was found in 27.2% of the patients. The prevalence of MS was 42.2%.
Women had significantly more abdominal obesity than men. Subjects with MS were significantly
older and predominantly females who had higher blood pressure and body mass index (BMI). CV
complications were more frequent among the MS subjects than among the controls. Glycemia,
triglycerides, total cholesterol and low-density lipoprotein-cholesterol (LDL-c) were significantly
higher in the group of CKD patients with MS. However, the occurrence of MS was not influenced
by the nature of nephropathy, the degree of the CKD and the use of reninangiotensin blockers or
statins. In multivariate analysis, predictors of occurrence of MS in our series included older age,
female gender and higher BMI and LDL-c levels. The prevalence of MS in patients with CKD is
higher than the general population. These patients should receive special multidisciplinary care to
limit CV complications.

Introduction problems. The most important established risk

Chronic kidney disease (CKD) and metabolic
syndrome (MS) are worldwide public health
Correspondence to:
Dr. Anis Belarbia
Department of Nephrology, Dialysis and
Transplantation, Sahlouls University
Hospital, 4054, Sousse, Tunisia
E-mail: belar_99@yahoo.fr
factors for CKD are diabetes and hypertension.
In addition, obesity and MS are independent
predictors of CKD.1 Microalbuminuria and
CKD are also considered as cardiovascular
(CV) risk factors. Several studies have dis-
cussed the relationship between MS and
CKD.2-14 The pathophysiology of this con-
dition is not well understood. The risk of renal
disease in individuals with MS can be related
to the presence of two factors: Hypertension
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932
and hyperglycemia. However, some data sug-
gest that MS is an independent cause of
CKD.10-14 Few studies have reported that per-
sons with mildly reduced kidney function are
at greater risk for CV disease, but it remains
unclear whether CKD contributes to prevalent
MS in the non-diabetic population. No studies
have focused on the elderly to evaluate the
relationship between the level of kidney func-
tion and the prevalence of MS.
The aim of the present study is to determine
the prevalence and independent predictors of
MS in patients with CKD, in addition to fac-
tors and conditions associated with MS and to
explore the relationship with CKD and its
progression.
Subjects and Methods
The current study is a cross-sectional survey
conducted in CKD patients enrolled between
April and June 2009. Patients with diabetes
mellitus were excluded from the study.
Basic data of the patients included age, gen-
der, systolic (S) blood pressure (BP), diastolic
(D) BP, cholesterol (chol), triglycerides (TG),
high-density lipoprotein (HDL) cholesterol,
low-density lipoprotein (LDL) cholesterol, fas-
ting blood glucose, proteinuria, serum crea-
tinine (Cr), albumin, calcium and phosphate,
uric acid and albumin, as well as estimated
glomerular filtration rate (eGFR), from the
simplified equation developed using Modifica-
tion of Diet in Renal Disease (MDRD) and
CockroftGault (CG) formula data, Cr levels
and eGFR at baseline and after six months.
Other data collected included family and per-
sonal history (diabetes, hypertension, family
nephropathy), type of nephropathy, CV com-
plications including left ventricular hyper-
trophy (LVH), coronary heart disease: Angina
or myocardial infarction (MI), stroke, heart
failure (HF) and arrhythmias (using cardio-
thoracic index on chest radiograph, signs of
LVH on EKG, the sonographic cardiac ejec-
tion fraction, impaired relaxation and presence
of septal hypertrophy) as well as medications:
Inhibitor of angiotensin-converting enzyme
(ACE), inhibitors of AT1 receptor of angio-
Belarbia A, Nouira S, Sahtout W, et al
tensin II (ARBs) and statins.
Hypertension was defined as a history of
hypertension (BP 140/90 mm Hg) that re-
quired the initiation of antihypertensive the-
rapy by the primary physician.
MS was defined according to the revised
criteria of the National Cholesterol Education
Program Adult Treatment Panel (NCEP-
ATPIII), which included individuals with three
or more of the following five components:
1) Central obesity: Waist circumference >102
cm in men or >88 cm in women with body
mass index (BMI) 25 kg/m2.
2) Hypertriglyceridemia: TG 150 mg/dL (1.7
mmol/L).
3) Low HDL-c <40 mg/dL (1 mmol/L) if the
patient is male and <50 mg/dL (1.3 mmol/
L) if female.
4) High BP 130/85 mm Hg and/or
5) High fasting glucose 110 mg/dL (6.11
mmol/L).
CKD was defined with an eGFR according to
the K/DOQI 2002 classification using the CG
formula:
Clearance of Cr = K weight (kg) [140-age
(y)]/Cr (mol/L); K = 1.04 for women and K =
1.23 for men.
MDRD formula:
For men = 186 (creatinine (mol/L)
0.0113)-1,154 age- 0,203
( 1.21 if African origin); 0.742 if woman
eGFR by MDRD was not calculated in five
patients who had Cr above 700 mol/L who
were considered to be at Stage 5 of CKD.
Schwartz formula (for children):
Clearance of Cr = K height (cm)/serum Cr
(mol/L)
K = 29 (newborns); 40 (infants); 49 (children
under 12 years); 53 (girls aged between 12 and
21 years); 62 (boys aged between 12 and 21
years).
Terms of use of this formula: Ages between
six months and 20 years and height between
40 and 200 cm. We used this formula in two
patients aged 15 and 16 years.
BMI: The International Classification.
BMI Classification
<18.5 Underweight
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Metabolic syndrome and chronic kidney disease
18.524.9 Normal weight
25.029.9 Overweight
30.034.9 Class I obesity
35.039.9 Class II obesity
40.0 Class III obesity
Statistical Analysis
All statistical analyses were performed using
SPSS and Excel softwares. Continuous data are
reported as mean SD (standard deviation). P
<0.05 is considered statistically significant.
The analytical study was conducted using
chi-square and chi-square-corrected (Fisher)
tests to compare qualitative variables, one-way
analysis of variance (ANOVA) to compare
quantitative variables for more than two
groups, independent-sample t test to compare
quantitative variables between two groups de-
pending on the assumed equality of variances
tested by the Levenes test F.
For the multivariate data analysis, we selec-
ted variables with a threshold
15% (P
0.150).
A logistic regression using the step-down pro-
cedure was applied to the collected data to
quantify the observed connections.
Only the parameters significantly related to
MS are presented as odds ratio, terminals of the
confidence interval at 95% and the value of P.
Results
The average age of our patients was 52.8
18.3 years, ranging from 15 to 83 years. The
average age was similar between genders (52.5
19.6 years for men and 53.2 16.7 years for
women); patients older than 65 years repre-
sented 29.4% of the total number of patients.
In our study, 101 (56.1%) patients were male,
with a sex ratio of 1.27; males were more fre-
quently represented in the age group >65
years. Family history of diabetes was found in
26 (14.4%) cases, which was the same for his-
tory of family nephropathy. History of hyper-
tension was found in 46 patients (25.5%). No
history of disease was found in 79 (43.9%) pa-
tients, 119 (66.1%) patients had hypertension,
14 (7.7%) patients had dyslipidemia and 12
(12%) patients had gout.
933
Analysis of the measurements of the anthro-
pometric parameters showed that the average
BMI was 27.3, with a range of 16.542, and
the average tissue thickness (TT) was 93.3 cm,
with a range from 62 to 130. The TT average in
males was 91.1 13.5 cm and that in females
was 96.2 14.2 cm. Most of our patients were
overweight (35.6%) or obese (28.3%). The
mean systolic blood pressure (SBP) and dias-
tolic blood pressure (DBP) and the anthro-
pometric characteristics of the patients are
summarized in Table 1.
The average of serum creatinine levels was
249 mol/L, with a Cr clearance of 55.8 (by
CG) and 46.7 (by MDRD). The average of
HDL levels was 0.98 mmol/L. The average of
TG levels was 1.38 mmol/L and the average of
fasting glucose was 5.27 mmol/L.
As for the used medications, 87 (48.3%) pa-
tients were on ACE inhibitors, 29 (16.1%) pa-
tients were on ARB and 22 (12.2%) patients
were on statins.
Major CV complications are summarized in
Figure 1. LVH was the most common compli-
cation observed in 33 (21.5%) of the study
patients.
MS was found in 76 (42%) patients. A more
detailed analysis of the number of criteria per
person revealed that the majority of the study
patients (34%) had two criteria of MS. In
patients with MS, criteria associations of MS
most frequently found were, in descending
order: 29 (38.15%) patients with TT + HDL +
hypertension, 11 (14.5%) patients with TT +
HDL + hypertension + TG and eight (10.5%)
patients with HDL + hypertension + TG.
The criterion of MS most common among
our patients was low HDL-c (67.8%), followed
by SBP (59.4%) and waist (46.1). In cases with
MS, the most frequent criteria were repre-
sented by the waist (75.9%), followed closely
by the SBP (73.6%) and TG (72.7%).
A study of the frequencies of the MS criteria
by gender found that SBP 130 mm Hg and
HDL <1.3 mmol/L were the two most com-
monly represented criteria, respectively, in
men and women. Women had more abdominal
obesity (P = 0.000), whereas men had more
hyperglycemia and high SBP.
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934 Belarbia A, Nouira S, Sahtout W, et al

Table 1. The main biological characteristics of the study patients.

Minimum Maximum Average Standard deviation
Creat (mol/L) 40 971 249 200.5
eGFR (CG) (mL/min) 4.38 220 55.8 49.2
eGFR (MDRD) (mL/min) 5.9 207 46.7 38.9
Serum calcium (mmol/L) 1.7 2.91 2.27 0.20
Serum phosphate (mmol/L) 0.66 2.56 1.39 0.39
Serum uric acid (mol/L) 214 741 430 110.8
Serum total cholesterol
2.5 11.3 4.95 1.62
(mmol/L)
TG (mmol/L) 0.11 5.78 1.38 0.86
HDL-c (mmol/L) 0.29 3.72 0.98 0.38
LDL-c (mmol/L) 0.92 8.13 3.29 1.37
Blood glucose (mmol/L) 3.8 7 5.27 0.82
PTH (pg/mL) 21.7 1094 339.4 303.2
Albumin (g/L) 8.8 50 30.9 9.3
Proteinuria (g/24 h) 0 12.4 1.99 3.01
Creat: Creatinine, CG: CockroftGault formula, MDRD: Modification of Diet in Renal Disease formula,
PTH: parathormone, TG: triglyceride, HDL: high-density lipoprotein, LDL: low-density lipoprotein.

MS was more frequently found in female
patients, with a statistically significant diffe-
rence (P = 0.000). Table 1 compares the ave-
rages of several physical and biological para-
meters studied according to the presence or
absence of MS.
The study of MS, based on the initial nephro-
pathy, showed no significant difference. The
patients with vascular nephropathy had more
MS: 60% versus 40% (P = 0.06).
Comparing the frequency of MS according to
the stage of CKD revealed no significant dif-
ference, regardless of the method of eGFR (CG
or MDRD, P = 0.8 and 0.28, respectively).
There was no significant difference in the
frequency of the use of ACE inhibitors, ARBs
or statins between the MS and non-MS groups.
The frequency of CV complications was
35.5% versus 21% for the MS and non-MS
groups, respectively (Table 2).
The logistic multi-regression analysis identi-
fied four independent predictors for the occur-
rence of MS in the CKD patients (Table 3).
The significant independent predictors of MS
included gender, age, BMI and HDL-c. How-
ever, there were no strong and significant cor-

Figure 1. The frequency of cardiovascular complications in the study patients.

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Metabolic syndrome and chronic kidney disease 935

Table 2. Criteria associations of MS.

Criteria associations Frequency (%)
TT + HTN + HDL 29 (38.15)
TT + HTn + HDL + TG 11 (14.47)
TG + HDL + HTN 8 (10.52)
HTN + HDL + hyperglycemia + TG 1 (1.3)
TT + HDL + hyperglycemia + TG 1 (1.3)
TT + HTN + hyperglycemia + TG 4 (3.9)
TT + HTN + TG 3 (3.9)
TT + TG + HDL 2 (2.6)
TT + HTN + hyperglycemia + HDL 7 (9.2)
TT + HTN + hyperglycemia 3 (3.9)
Hyperglycemia + HTN + TG 1 (1.3)
Hyperglycemia + HTN + HDL 2 (2.6)
TT + HTN + hyperglycemia + TG + HDL 4 (5.2)
TT: Tissue thickness, HTN: hypertension, TG: triglyceride, HDL: high-density lipoprotein, LDL: low-
density lipoprotein.

relations between MS and the initial nephro-
pathy.
Serum Cr and its clearance were reassessed
after six months in only 148 patients. Com-
paring the evolution of renal function accor-
ding to the presence or absence of the MS did
not show any significant difference (Table 4).
Discussion
It is now clear that CKD increases the risk of
occurrence of CV complications. On the other
hand, MS is a powerful CV risk factor. Cur-
rent studies have demonstrated the deleterious
effect of this syndrome on the kidney. How-
ever, the relationship of cause and effect bet-
ween MS and CKD is still a subject of debate.
Using the NCEP ATPIII definition, MS was
found in 42.2% of our patients. We choose this
Table 3. Comparison of metabolic syndrome (MS) in the general population and our study.
Criteria of SM General population
Blood glucose 6.1 mmol/L
TG 1.7 mmol/L
Systolic BP 130 mm Hg
Diastolic BP 85 mm Hg
Waist
>102 cm (men)
>88 cm (women)
HDL-c
<1 mmol/L (men)
<1.3 mmol/L (women)
TG: Triglyceride, BP: blood pressure, HDL: high-density lipoprotein.
definition because it is the most commonly
used definition in the medical literature. Con-
cerning the other definitions, the World
Health Organization or WHOs definition is
not adapted to our population. The definition
of International Diabetes Federation or IDF
with lower values of TT and blood sugar may
overestimate the prevalence of MS.1 This pre-
valence was lower in the general Tunisian
population. Indeed, the Tunisian studies esti-
mated that 18% of women and 13% of men
had MS.1
According to the WHO definition, David2
found that the prevalence of MS was 30.5%,
while knowing that he had included patients
with diabetes and dialyzed patients. The AASK
study3 found a prevalence of 41.7% among
AfricanAmericans with vascular nephropathy,
which is consistent with our results.
Patients with MS
13.9 30.2
24.4 72.7
59.4 73.6
37.2 52.6
46.1 75.9
67.8 50.8
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936 Belarbia A, Nouira S, Sahtout W, et al

Table 4. Comparison between the averages of various physical and biological parameters studied
according to the presence or absence of metabolic syndrome (MS).
Parameters MS present MS absent P
Weight (kg) 80.3 17.4 69.1 15.1 0.000
BMI (kg/m) 30.7 5.4 24.9 4.6 0.000
Age (years) 59.5 15.5 47.9 18.7 0.000
Systolic BP (mm Hg) 140.1 21.9 128 23.5 0.001
Diastolic BP (mm Hg) 86.5 15 80.8 12.3 0.009
Waist 102 11.9 87.0 11.9 0.000
Glycemia (mmol/L) 5.57 0.95 5.04 0.62 0.000
Cholesterol (mmol/L) 5.39 1.58 4.63 1.57 0.002
TG (mmol/L) 1.70 0.91 1.15 0.75 0.000
HDL-c (mmol/L) 0.94 0.29 1.02 0.44 0.218
LDL-c (mmol/L) 3.6 1.37 3.06 1.33 0.008
Uric acid (mol/L) 437 97.19 425 119 0.574
Serum albumin (g/L) 31.6 9.60 30.5 9.28 0.657
PTH (pg/mL) 312 287 347 312 0.794
Proteinuria (g/24 h) 1.59 2.66 2.29 3.24 0.215
BUN (mmol/L) 13.7 11.30 13.7 9.81 0.998
Creat (mol/L) 223 176 268 216 0.138
Cl CG (mL/min) 55.7 46.8 56.0 51.1 0.968
Cl MDRD (mL/min) 43.4 32.3 49.3 43.3 0.326
BMI: Body mass index, BP: blood pressure, TG: triglyceride, HDL: high-density lipoprotein, LDL: low-
density lipoprotein, PTH: parathormone, BUN: blood urea nitrogen, Creat: creatinine, CG: Cockroft
Gault formula, MDRD: Modification of Diet in Renal Disease formula.

There is variability in the prevalence of MS difference in the BP in two studies of MS in

that could be explained by ethnic differences
and the different definitions of the disease,18-26
which results in the difficulty in comparing
studies that do not use the same definition.25,26
Patients with MS were older in our study.
These results were found in most of the se-
ries.1,2,4-6,9,11-13,27,28 Age was an independent risk
factor for the occurrence of MS in our study.
MS was significantly more common in
females in our study, as those included in other
Tunisian studies.1,4,5,15-17,28 However, MS was
significantly more common among men in
other Asian series9,11,12 and in the French
DESIR study.10 In contrast, there was no signi-
ficant difference in gender in the ARIC study,4
African Americans3 and the Australian study.2
In our study, female gender was an indepen-
dent risk factor for the occurrence of MS in the
CKD patients.
The SBP and DBP were significantly higher
in patients who had MS in our study. These
results are consistent with the literature data.4-
7,9,11-13,17,27,28
However, there was no significant
CKD patients.2,3
In our study, the mean BMI was significantly
higher in patients with MS. Most previous
studies found similar results.2-7,9,11-13,27,28 BMI
was also an independent factor for the occur-
rence of MS in our patients. Recent studies
have shown that obesity may be an inde-
pendent risk factor for the progression of
CKD29-31 even without diabetes and hyperten-
sion. This could be explained by glomerular
hyperfiltration, which results in glomerular
sclerosis.32 Pro-inflammatory cytokines secre-
ted by adipose tissue (interleukin-6, tumor
necrosis factor-alfa) and angiotensin II33 can
also play an important role in the genesis of
glomerulosclerosis.34
Waist was significantly higher in patients
with MS in our study, which is consistent with
the results from the literature.4-7,9,12,13,27,28
Abdominal obesity by the measured waist is
considered in some studies as the initiator of
MS, as it would cause insulin resistance.4,10,32,35-
39
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Metabolic syndrome and chronic kidney disease
Abdominal obesity differs from the other
types of obesity because of its metabolic
characteristics. Indeed, it is composed of larger
adipocytes, more insulin resistance and higher
TG. Abdominal obesity is also associated with
an increase in free fatty acids, reduction of
adiponectin, resistance of peripheral tissues to
the action of leptin and infiltration of adipose
tissue by macrophage cells with release of
inflammatory cytokines.35
Our patients had low average eGFR com-
pared with those in the literature because of
the type of population with CKD.3,6,8,11,12,28 In
our study, the analysis of renal function did
not find a significant difference of the fre-
quency of MS between the CKD and non-
CKD patients. The studies performed in pa-
tients without CKD found the same result.6,12
Similarly, in the AASK cohort,3 whose pur-
pose was to evaluate the influence of MS on
the progression of CKD in hypertensive
AfricanAmericans, the CL Cr was 45.5
13.6 mL/min for those with MS versus 46
12.7 mL/min for those without MS. In con-
trast, other series4,5,7,9,11,13,17,27,28,40 found that
patients with MS had significantly lower Cl Cr
compared with those without MS. These
studies concluded that MS is an independent
risk factor for the occurrence of CKD. In fact,
after a few years of follow-up (512 years
depending on the study), patients with MS had
a higher incidence of CKD,4,7,11,12,13,41,42 even
in the absence of diabetes4,7,12 or hypertension.7
Unlike the data from several studies, there
was no significant difference in HDL-c bet-
ween patients with MS and patients with-out
MS, may be because of the CKD. In our se-
ries, LDL-c was an independent risk factor for
the occurrence of MS. Now, it is well known
that LDL-c and persistent inflammatory sti-
muli result in the formation of foam cells and
mesangial cells that do not properly contract
and secrete an extracellular matrix that even-
tually contributes to glomerulosclerosis.43
In our study, the patients with MS had signi-
ficantly more CV complications than those
without MS. This is consistent with the litera-
ture data.44-50 Indeed, several cohorts studied
the relationship between MS and the occur-
937
rence of CV events. These studies found that
MS patients were two to three times more
likely to develop CV events independently of
the presence of diabetes, regardless of gender
and tobacco.44-46 Although MS is a vascular
risk situation, some authors47,51-56 believe that
this concept is not a better predictor of the CV
risk than the different individual parameters
used to define it. They also think that it adds
nothing in terms of predicting events in
relation to the use of the classical risk equa-
tions such as the Framinghams equation.47,53,54
In a British study,54 this score was even a
better predictor of coronary heart disease and
stroke compared with MS. The reason for this
superiority of the Framingham score is that it
quantifies the risk. Indeed, the amplitude of
anomalies contributes to the risk level. This
amplitude is not taken into account in the
definition of MS.47
In our study, the majority of the patients had
two criteria of MS (34%). The patients without
any criteria accounted for 6.1%, and those with
more than four criteria accounted for 15%.
Other studies reported similar results.4,11,19
Finally, there was selection bias related to the
reduced number of patients and the hetero-
geneity of the population (we included in the
study patients with different stages of CKD).
In addition, the duration of follow-up is short
(6 months).
We conclude that the prevalence of MS in
patients with chronic renal failure is high.
Predictors of the occurrence of MS in our
study included older age, female gender and
higher BMI and LDL-c levels. The CV
complications were more frequent among the
MS patients. Furthermore, larger prospective
studies to analyze the effect of the overall
management of MS on the progression of
CKD are warranted.
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