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THE EVALUATION OF NEPHROPATHY RISK FACTORS
IN TYPE 2 DIABETES
Short title: The risk factors of Nepropathy in diabetes.
Tahsin Çelepkolu1,
Mehmet Halis Tanrıverdi1,
Sercan Bulut Çelik²,
Pakize Gamze Erten Bucaktepe¹,
Hüseyin Can³,
Ilknur Aslan4
Erkan Kıbrıslı1
Enver Erdem5
Faruk Kılınç6
1
Department of Family Medicine, Dicle University Medical Faculty, Diyarbakır, Turkey.
2
11th Family Health Center, Batman, Turkey.
3
Department of Family Medicine, Katip Çelebi University Medical Faculty, İzmir, Turkey.
4
Mazgirt Integrated Town Hospital, Tunceli. Turkey
5
Siyavuşpaşa Family Health Center, Bahçelievler, İstanbul, Turkey.
6
Department of Endocrinology and Metabolism, Dicle University Medical Faculty,
Diyarbakır, Turkey
Corresponding Adress:
Assist. Prof. Dr. Tahsin Çelepkolu
Dicle University Medical Faculty,
Department of Family Medicine
21280-Diyarbakır
Tel: 0412-2488001/4643
E-mail: [email protected]
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Abstract
Introduction: The prevalence of diabetes has been increasing at an alarming rate around the
world. Thus, the complications of diabetes are increasingly prevalent and each year three
million people die as a result of chronic complications of diabetes. In Turkey, the prevalence
of diabetes was 7.2% in 2000, and had increased to 13.7% by 2010. In our study, we aimed to
compare nephropathic and nonnephropathic patients according to sociodemographic features,
biochemical parameters, and proteinuria characteristics.
Methods: Between January 2000 and December 2008, 923 type 2 diabetic patients data were
analyzed retrospectively. The records of 378 patients were included in the study and classified
as normoalbuminuric, microalbuminuric and macroalbuminuric. These groups were compared
in terms of demographic, clinical and laboratory findins to investigate the risk factors related
to nephropathy.
Results: Of the 378 patients, 224 were female (59%) and 154 were male (41%). The mean
age was 58.9±9.7 years. A total of 100 patients (26.5%) with micro- and macroalbumiuria
were identified as nephropathic. The diabetic nephropathic patients were divided into two
groups, microalbuminuric (n=80) and macroalbuminuric (n=20). In the nephropathic group,
the levels of FBG, PBG, HbA1c, urea, and creatinine, and the duration of known diabetes
were significantly increased when compared with the non-nephropathic group. Diastolic
blood pressure and urea levels were significantly higher and creatinine clearence was
significantly lower in the macroalbuminuric group.
Conclusion: We found a significant relationship between nephropathy and HbA1c, an
important indicator of blood glucose control. Therefore, it is essential to provide aggressive
blood pressure management and long-term glycemic control in order to reduce cardiovascular
risk, prevent the development of diabetic nephropathy and ESRF, and reduce overall mortality
and morbidity. Education of diabetic patients on the risks and complications of elevated blood
pressure and poor gycemic control is a critical component of clinical practice.
Keywords: Nepropathy, risk factors, diabetes.
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INTRODUCTION
The prevalence of diabetes is increasing considerably and without impediment around the
world (1,2). Diabetic complications are also more prevalent than ever before, and three
million people die as a result of chronic diabetic complications each year (3). Diabetic
nephropathy is the most prominent cause of end stage renal failure (ESRF) in the United
States and Europe (4). The prevalence of diabetes in Turkey was 7.2 % in 2000, and had
increased to 13.7 % by 2010 (5,6). According to the records of the Turkish Nephrology
Association, 25.2 % of newly diagnosed ESRF patients in Turkey have diabetes (7).
Declining quality of life is associated with the complications of diabetes, which may include
depression particularly among patients with neuropathy (8). Nephropathy is a microvascular
complication of diabetes, and one of the earliest findings of nephropathy is microalbuminuria
(9). In some patients with type 2 diabetes and nephropathy, cardiovascular disease may cause
death before the development of ESRF (10). Type 2 diabetes may develop and progress
without notice, and microalbuminurea can develop 12-20 years prior to diabetes diagnosis in
some cases (5,9).
In the present study age, gender, duration of known diabetes , family history, HbA1c, lipid
parameters, fasting blood glucose, postprandial blood glucose, systolic and diastolic artery
pressure, urea, creatinine, body mass index and creatinine clearance were compared among
normoalbuminuric, microalbuminuric, and macroalbuminuric diabetics in the diabetes clinic
of İstanbul Bezm-i Alem Valide Sultan Training and Research Hospital and the risk factors
related to nephropathy were evaluated.
METHOD
The data was obtained from the retrospective investigation of outpatient follow-up records of
923 type 2 diabetics who presented at the outpatient diabetes clinic of İstanbul Vakif Gureba
Education and Research Hospital between Jaunary 2000 and December 2008. Of this group,
378 patients whose records included all our study parameters were included in our analysis.
Age, gender, duration of known diabetes , height, weight, body mass index (BMI), fasting
blood glucose, postprandial blood glucose, systolic blood pressure, diastolic blood pressure,
total
cholesterol,
LDL-cholesterol,
VLDL-cholesterol,
triglyceride,
HbA1c,
microalbuminurea, creatinine clearance, urea and creatinine values in a 24-hour urine sample
were recorded for each of the 378 patients included in the study. Family history of diabetes
was determined according the initial history given by each patient.
In the beginning, the patients were classified as those with diabetic nephropathy (>30 mg/24
hour albuminurea) and those without diabetic nephropathy (<30 mg/24 hour albuminurea). In
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addition, the group with diabetic nephropathy was divided into two groups as individuals with
microalbuminurea (30-300 mg/24 hour albuminurea) and individuals with macroalbuminurea
(>300 mg/24 hour albuminurea). Thus, three subgroups were obtained from the group of
patients
with
diabetic
nephropathy:
normoalbuminuric,
microalbuminuric
and
macroalbuminuric. These groups were compared according to the clinical parameters listed
above.
The chronological age that the patients declared upon initial presentation to the diabetes clinic
was used in the evaluation. The weight of each patient, with clothing on, was recorded in
kilograms on the clinic scale with clothing on and the height of each patient, without shoes,
was recorded in meters. In cases where creatinine clearance had not been calculated, the
Cockroft-Gault formula was used. BMI was calculated as weight (kg)/height(m)2. Duration of
known diabetes was noted in years. Blood pressure was recorded by taking the average of two
measurements through an indirect method with a desktop sphygmomanometer (Erkameter
3000 with standard mercury) when the patient sitting erect, had rested for five minutes and
did not smoke or drink coffee or tea in the last one hour. Biochemical and hormonal
parameters were recorded using an Immulite-2000 device. The parameters recorded included
fasting blood glucose (FBG), postprandial blood glucose (PBG), total cholesterol, LDLcholesterol, HDL-cholesterol, triglyceride, and urea. The level of creatinine was determined
by ECLIA (electro chemiluminescent immunoassay) in the Biochemistary Laboratory of
Vakıf Gureba Training and Research Hospital and HbA1C level was determined using
Boronat afinity-HPLC (high performance liquid chromatography) and an Abbott G 800
autoanalyser. The concentration of microalbumin in the 24-hour urine sample was determined
by the ECLIA method.
Statistical analysis of the data was completed using SPSS 15.0 for Windows. The normality of
all data was tested by Kolmogorov–Smirnov test. Descriptive statistical results of the study
data were expressed as arithmetical average ± standard deviation for normally distributed
variables. For non-normally distributed parameters, central measures were expressed as
median (min-max). While evaluating groups, distribution of patients is given as frequencies.
The Student’s t-test was used for the comparison of normally distributed data, and the Mann
Whitney-U test was used for comparison of variables that did not adhere to a normal
distribution.
In the analysis of qualitative data, the Pearson chi-square test and correlation
analysis were used. In evaluating the results obtained from the statistical tests, 95 %
confidence interval and
p value less than 0.05 (<5 %) was accepted as statistically
meaningful.
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RESULTS
Three hundred seventy eight of 923 patients (224 female (59%) and 154 male (41%) ) had
complete clinical rescords of all the study parameters and were included in the study. The age
average of the patients was 58.9±9.7 years. The distribution of the patients according to
albumin level in a 24-hour urine sample is shown in Figure 1.
The average duration of diabetes was 11.70 ± 6.87 years, average Hemoglobin A1c level was
8.49±1.89%, average systolic blood pressure was 139.78±73.63 mmHg, average diastolic
blood pressure was 83.33±11.27, average LDL-cholesterol level was 126.47±40.91 mg/dl,
average HDL-cholesterol level was 48.97±15.85 mg/dl, average triglyceride level was
218.17±121.01 mg/dl, and average BMI was 32.09±5.40.
A hundred patients with micro- and macroalbuminurea were identified as diabetic with
nephropathy (26.5%). The number of patients in non-nephropathic group was 278 (73.5 %).
The mean values and p values for the comparison of parameters between these two groups are
shown in Table 1.
Diabetic patients who comprised the diabetic nephropathy group were divided into two
groups as microalbuminuric (n=80, 21.2 %) and macroalbuminuric (n=20, 5.3 %) according
to the difference in microalbumin level in a 24-hour urine sample were compared in terms of
several parameters and the results of this comparison are shown in Table 2.
DISCUSSION
The incidence and prevalence of diabetes is in increasing wordwide as well as within Turkey.
As a result, the incidence of microvascular and macrovascular complications of diabetes has
been increasing as well (11). Among these, diabetic nephropathy is especially important.
Diabetic nephropathy is the most common cause of ESRF in the USA, Europe and Japan (12).
At least 20-30 % of type 2 diabetics subsequently develop diabetic nephropathy (13). We
observed nephropathy (patients with micro and macroproteinurea) in 26 % of the patients
included in this study.
Diagnosis may be delayed in type 2 diabetics, and microalbuminurea and clinical nephropathy
may be observed in newly diagnosed patients if diabetes has been present in the patient for
many years prior to diagnosis. Moreover, microalbuminurea results in increased risk of
cardiovascular morbidity and mortality. Microalbuminurea is correlated with increased blood
pressure in addition to other factors such as age, gender, duration of diabetes, body mass
index, and glycemic control (14). The frequency of microalbuminurea and macroalbuminurea
in our study population were 21.2 % and 5.3%, respectively.
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The relationship between diabetic nephropathy and diabetes duration has examined in
numerous studies. When diabetes persists longer than 10 years, the incidence of diabetic
nephropathy begins to increase dramatically and may be as high as 50% (9). In our study, the
percentage of patients with diabetes duration of longer than 10 years was 54 %. However, 45
% of patients in the nonnephropathic group had diabetes for at least 10 years, an observation
that was statistically meaningful.
The most significant risk factors for nephropathy in diabetic patients are elevated HbA1c and
hypertension (15,16). In our study, HbA1c was significantly increased in the nephropathic
group (p< 0.05).
In the published literature, diabetic nephropathy has been associated with poor glycemic
control, hypertension and dyslipidemia (17,18). In our study, fasting and postprandial blood
glucose levels were higher among the nephropathic group. Comparing systolic and diastolic
blood pressures, a slight increase was observed in the nephropathic group that was not
statistically significant. Many of the patients in this group used antihypertensive medications.
Our analysis indicated that there was no meaningful diffence in total cholesterol and
triglyceride levels between the patients. Triglyceride values were elevated in both groups,
however, there was no statistically significant difference.
The study performed by Bruno et al. on 1586 type 2 diabetes detected an increased prevalence
of micro- and macroalbuminurea among male patients compared to female patients. Relative
to normoalbuminuric patients, age, gender, diabetes duration, fasting glycemia, Hb1Ac,
triglyceride
and uric
acid
levels
ere increased in
both
microalbuminuric and
macroalbuminuric patients. Moreover, plasma LDL and creatinine levels were increased and
HDL-cholesterol levels were decreased in macroalbuminuric patients. There was no
difference in fasting blood glucose and Hb1Ac between micro- and macroalbuminurea
patients, however both parameters were slightly elevated relative to normoalbuminuric cases.
In the light of these results, many researchers have concluded that microalbuminurea is
already present when type 2 diabetes develops and diabetes has a role in the transition from
macroalbuminurea to microalbuminurea (19,20). In our study, diabetic nephropathy is
significantly more common in male patients (54 %) and diabetes duration, fasting glycemia,
HbA1c, triglyceride and uric acid levels were elevated in macro- and microalbuminurea
compared to patients with normal albuminurea.
In a seven year study following 135 type 2 diabetes patients suffering from the disease for
more than 30 years, Arun et al. reported that 33% of microalbuminuric patients and 83.3%
of proteinuric patients died during the period of follow up, concluding that albuminurea and
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BMI are the independent risk factors of early death (21,22). When we compared the groups in
terms of body mass index, we found an increase in BMI among the nephropathic group that
was not statistically significant (p>0.05).
In the RENAAL study patients the risk of ESRF or death was increased by 38% among
patients with an initial systolic blood pressure of 140-159 mmHg compared to patients with
systolic blood pressure <130 mmHg (23). In our study, diastolic blood pressure was
significantly higher in the macroalbuminuric group.
In a 5.8 year follow up study of 191 normoalbuminuric type 2 diabetic patients performed
prospectively,Gall and his colleagues from the Steno Diabetes Center found that the main risk
factor defining the development of persistent micro- and macroalbuminurea was initial total
cholesterol. This variable was an independent risk factor in the development of diabetic
nephropathy (24). In our study, while there was no difference between the groups according
to LDL-cholesterol and HDL-cholesterol, triglyceride levels were significantly higher in the
macroalbuminuric group.
We found a significant relationship between nephropathy and HbA1c, an important indicator
of blood glucose control. Therefore, it is essential to provide aggressive blood pressure
management and long-term glycemic control in order to reduce cardiovascular risk, prevent
the development of diabetic nephropathy and ESRF, and reduce overall mortality and
morbidity. Education of diabetic patients on the risks and complications of elevated blood
pressure and poor gycemic control is a critical component of clinical practice.
Conflict Interests
The authors declared no conflict of interest.
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Table and Figure legends:
Table 1: Comparison of the Nephropathic and Non-nephropathic groups
Table 2: Comparison of Microalbuminuric and Macroalbuminuric diabetics
Figure 1: The distribution of the patients according to albuminurea level (n=378)
10
Graphic 1: The distribution of the patients according to albuminurea level (n=378)
80 (21.2%)
20 (5.3%)
Normoalbuminurea
Microalbuminurea
Macroalbuminurea
278 (73.5%)
11
Table 1: The Comparison of the Nephropathic and Nonnephropathic groups
Nephropathy (+)
Nephropathy (-)
P
(n=100)
(n=278)
59.70 ± 11.38
58.56 ± 9.03
<0.05
Age
54/46
100/178
<0.01
Gender (M/F)
216.70 ± 76.80
196.99 ± 72.54
<0.05
FBG
314.77 ± 116.72
280.36 ± 101.69
<0.05
PBG
8.85 ± 1.94
7.94 ± 1.75
<0.05
HbA1c
14.08 ± 8.04
11.11 ± 6.32
<0.05
Diabetes age
31.5 ± 6.1
30.8 ± 5.1
NS
BMI
139.93 ± 22.22
139.73 ± 24.76
NS
Systolic blood pressure
82.96 ± 10.60
81.01 ± 11.47
NS
Diastolic blood pressure
217.64 ± 77.88
209.77 ± 48.03
NS
Total cholesterol
128.91
±
39.16
128.36
±
41.59
NS
LDL-cholesterol
47.05 ± 18.70
45.93 ± 14.72
NS
HDL-cholesterol
213.72 ± 152.53
188.21 ± 106.91
NS
Triglyceride
40.45 ± 18.34
34.73 ± 13.37
<0.05
Urea
1.18 ± 0.50
0.91 ± 0.28
<0.05
Creatinine
79.52 ± 32.98
98.06 ± 8.46
<0.05
Creatinin Clearence
68 (68.0%)
190 (68.3%)
NS
Family history (+)
FBG: Fasting Blood Glucose, PBG: Post Prandial Glucose, BMI: Body Mass Index, LDL:
Low denstiy lipoprotein, HDL: High density lipoproteion, NS: Not significant.
Related parameter
12
Table 2: The Comparison of Microalbuminuric and Macroalbuminuric groups
Related parameter
Microalbuminurea Macroalbuminurea
p
(n=80)
(n=20)
60.16
±
11.88
57.85
±
8.76
0.021
Age
47/33
7/13
Gender (M/F)
216.09 ± 75.49
219.15 ± 88.98
FBG
311.46 ± 110.66
327.85 ± 140.62
PBG
NS
8.89 ± 2.05
8.79 ± 1.45
HbA1c
12.82 ± 8.06
15.35 ± 7.81
Diabetes age
30.59 ± 5.28
34.87 ± 6.21
BMI
136.08 ± 20.90
145.25 ± 26.13
NS
Systolic blood pressure
81.56 ± 10.37
88.50 ± 9.88
NS
Diastolic blood pressure
217.64 ± 77.88
209.77 ± 48.03
Total cholesterol
129.01
±
39.68
128.36 ± 41.59
LDL-cholesterol
NS
44.47 ± 10.06
45.93 ± 14.72
HDL-cholesterol
200.54 ± 128.99
188.21 ± 106.91
Triglyceride
36.79 ± 12.25
55.10 ± 29.10
0.012
Urea
1.01 ± 0.25
1.46 ± 0.93
NS
Creatinine
93.69 ± 31.12
72.85 ± 35.70
0.011
Creatinine clearence
13 (65.0%)
NS
Diabetes positive family history 55 (68.8%)
FBG: Fasting Blood Glucose, PBG: Post Prandial Glucose, BMI: Body Mass Index, LDL:
Low denstiy lipoprotein, HDL: High density lipoproteion, NS: Not significant.
13