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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] 1 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. 2 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 3 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. 4 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. 5 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 6 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. REFERENCES 1. Powers AC. Diabetes Mellitus. Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL. Harrison’s Principles of Internal Medicine. 16th ed. USA: McGraw Hill, 2005;2152-80. 2. Warram JH, Krolewski WC. Epidemiology of diabetes mellitus. Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ. Joslin’s diabetes mellitus. 14th ed. Boston: Lippincott Williams&Wilkins, 2005;341-54. 3. Gross JL, De Azevedo MJ, Silveiro SP et al. Diabetic Nephropathy: Diagnosis, Prevention and Treatment. Diabetes Care 2005:28(1)164-176. 4. Retnakaran R, Cull CA, Thorne KI et al. (UKPDS Group 74). Risk Factors for Renal Dysfunction in Type 2 Diabetes. Diabetes 2006;1(2)30-37. 7 5. Satman I, Yılmaz T, Sengul A, et al. Population-based study of diabetes and risk characteristics in Turkey: Results of the Turkish diabetes epidemiyology study (TURDEP). Diabetes Care 2002;25:1551-1556. 6. Satman İ and TURDEP II Working Group 47. Ulusal Diyabet Kongresi -TURDEP II Sonuçları- 11-15 Mayıs 2011. 7. Büyükdevrim AS, Büyükbeşe MA, Davutoğlu M. Tanımı ve Sıklığı, Diyabetik Nefropati. Birinci baskı, Turgut Yayıncılık A.Ş. 2005;8-11. 8. Eren MA, Torun AN, Tabur S, et al. The relationship between microvascular complications and depression in patients with type 2 diabetes mellitus who use insulin, Journal of Clinical and Experimental Investigations, 2013;4(1):34-39 9. Büyükdevrim AS, Büyükbeşe MA, Davutoğlu M. Korunma, Klasik Tedavi, Yeni Tedavi Girişimleri ve Geleceğe Yönelik Ümitlerimiz, Diyabetik Nefropati. Turgut Yayıncılık A.Ş. 2005(1);431-533. 10. Evrenkaya R. Diyabetik Nefropati. Özata M, Yönem A. Endokrinoloji-Metabolizma ve Diyabet. İstanbul Medikal Yayıncılık 2006(1);359-366. 11. Lasaridis AN, Sarafidis PA. Diabetic Nephropaty and Antihypertensive Treatment: What are the Lessons From Clinical Trials? Am J Hypertens. 2003;16:689-697. 12. Renal Data Sistem. USRDS 2000 annual data report. Bethesda: National Institute of Diabetes and Digestive and Kidney Disease 2001. 13. European Dialysis and Transplant Association. Report on management of renal failurein Europe, XXVI,1995. Nephrol Dial Transplant. 1996;11:1-32. 14. American Diabetes Association: Standarts of medical care in diabetes(Position Statement). Diabetes Care 27 (Suppl.1): S65-D67, 2004). 15. Murussi M, Baglio P, Gross JL, Silveiro SP. Risk Factors for Microalbuminuria and Macroalbuminuria in Type 2 Diabetic Patients. Diabetes Care. 2002;25:1101-1103 16. Selvin E, Wattanakit K, Steffes MW, Coresh J,Sharrett AR. HbA1c and peripheral arteriel disease in diabetes: the atherosclerosis risk in communities study. Diabetes Care 2006; 29:877-882. 17. Gres TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertansive terapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in communities Study. N Eng J Med 2000;342:905-12. 18. Hasslacher C, Bosted-Kiesel A, Kepme HP, Wahl P: Effect of metabolic factors and blood pressure on kidney function in proteinuric type2 diabetic patients. Diabetologia 1993 ;36:1051-1056. 8 19. Mulec H, Johnsen SA, Wiklund O, Bjorck S: Cholesterol: a risk factor in diabetic nephropthy. Am J Kidney Dis. 1993;22:196-201 20. Chen HC, Guh JM, Hsieh MC, et al. Role of lipid control in diabetic nephropathy. Kidney Int Suppl. 2005;94:60-62. 21. Bruno G, Cavallo-Perin P, Bargero G et al. Prevelans and risk factors for micro- and macroalbuminuria in an Italian population-based cohort of NIDDM subjects. Diabetes Care 1996;19:43-47. 22. Arun CS, Stoddart J, M ackin P et al. Significance of microalbuminuria in long-duration type1 diabetes. Diabetes Care 2003;26:2144-2149. 23. Bacris GL, Weir MR, Shanifar S et al. Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch Intern Med. 2003;163:15551565. 24. Gall MA, Hougaard P, Borch-Johnsen K, Parving HH: Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study. BMJ 1997;314:783-788. 9 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