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Compression of Angiotensin Receptor Blocker and Angiotensin Receptor Blocker along with N-acetyl Cysteine administration on reducing proteinuria in patients with type-II diabetes mellitus Abstract: Background:Proteinuria and albuminuria are established risk factors for progressive renal damage. Albuminuria can be effectively controlled with antihypertensive drugs that interrupt the renin-angiotensin –aldostrone system (RAAS). The efficiency of N-acetyl Cysteine (NAC) in preventing diabetic nephropathy is uncertain. Renoprotective effects of angiotensin receptor blocker and N-acetyl Cysteine (NAC) in preventing or reducing proteinuria in patients with diabetic nephropathy have been studied. Methods: In a randomized clinical trial study, 70 patients with type II diabetes nephropathy (Proteinuria and renal insufficiency) were studied. The patients were randomly divided into two groups (35 patients in each group) and matched considering sex, age, Hb A1C and fasting blood glucose. Then, they were treated with Losartan (25 mg twice a day) along with N-acetyl Cysteine (NAC) (600 mg twice a day) as case group.The control group were treated just with Losartan (25 mg twice a day). Urine protein was checked before treatment and two months later. Results: There were 35 patients (with mean age of 60.2±10.1 years and male to female ratio was 19/16) in the case group. The mean age of control group was 63.4±6.4 and male to female ratio was 20/15. Considering sex and age, there was no statistically significant difference between these two groups. But inter group studies revealed that mean proteinuria level decreased more than control group during study but comparison of proteinuria after 2 months showed no 1 statistical difference in studied time points between two groups (P=0.5). However proteinuria was decreased in both groups . Conclusion: According to results ARB and ARB+NAC reduced proteinuria due to diabetic nephropathy by the way therapy with ARB was not more effective than ARB alone. Keywords: Proteinuria, N-acetyl Cysteine,Angiotensin II, Type II Diabetes mellitus. 2 Introduction Diabetic nephropathy is one of the most important causes of chronic renal damage .There is strong relationship with cardiovascular diseases in patients with diabetic nephropathy .Proteinuria increases the morbidity rate of these patients (1). In 1980, it was first recognized that excreting of albumin even in lesser amounts (which can be evaluated by sensitive protein measuring methods ) may be regarded as an important predicting factor in renal insufficiency of patients with types I and II diabetes mellitus. Earlier stage of renal involvement is called microalbuminoria (2). Proteinuria is seen in about 15-40% of type I diabetic patients. The prevalence is more variable in type II DM and occurs in about 5-20% of patient. But number of patients with type 2 DM is increasing maybe due to better managing of these patients. For this reason we decided to select these patients as target in our study. According to previous studies blockage of renin-angiotensin-aldostrone system (RAAS) leads to stabilization or prevention of diabetic nephropathy. Also some types of non-diabetic nephropathies may be controlled during blocking of RAAS. However, follow up of the patients with type II diabetes demonstrates that moving toward renal chronic damage is often seen due to increasing number of these patients and this important complication of DM wastes a great amount of health expenditures in all parts of the world (3-5). Angiotensin-reseptor blockers (ARB) lead to reduction of renal capillary pressure with blocking of angiotensin-rennin-aldostrone system and prevent microalbuminuria progression and finally chronic renal damage (6). Rippin showed that protective effects of angiotensin receptor blocker are similar to angiotensin converting enzyme inhibitors in diabetic patients with proteinuria (27). Many different studies revealed that ARBs prevent or reduce proteinuria and finally chronic renal damage in type 2 diabetic patients (25, 26). Parving showed that ARBs prevent progression of microalbuminuria toward macroalbuminuria (28). 3 N-Acetyl Cysteine (NAC) is an antioxidant and relative vasodilator .This drug in different experimental animal studies revealed reduction of ischemia in acute kidney damages, improved glomerular filtration rate (GFR) and shortened recovery period (7-10). Renal toxicity of contrast agents remains an up-to-date challenge. N-Acetyl cysteine is an antioxyde agent which efficacy has been proved in various models of experimental renal ischemia and therefore proposed in the prevention of renal failure due to intravenous iodine contrast media (29). This type of study in human being (role of NAC in diabetic nephropathy and proteinuria) is not frequent and also resuls are controversial(11-14) Effective role of RAAS blocking drugs in diabetic patients with proteinuria and diabetic nephropathy is obvious and the main goal of this study is possible augmentation of these results with N-acetyl cysteine . Methods This randomized clinical trial study was conducted in Imam Reza and Sina teaching hospitals and Sheikholraeis Sub-specialized Clinic related to Tabriz university of medical sciences, Iran, during September 2010 to May 2011. Seventy patients with type 2 diabetes mellitus were enrolled in this study. All of them referred to our centers due to different stages of diabetic nephropathy. These patients randomly divided into two separate groups (each one consist of 35 patients).All of them had obvious proteinuria. The exclusion criteria were those patients consumed the drug irregularly, patients with serum creatinine level greater than1.8 mg/dl, patients with underlying problems affecting the kidney function and proteinuria. Two groups were matched considering age, sex and HbA1C serum level. Urinanalysis was done and FBS, HbA1C and 24-hour urine protein levels were measured before intervention. Then, Losartan (25 mg twice a day) for control group and angiotensin receptor blocker (ARB) at the same dosage along with NAC ( 600 mg twice a day) for case group 4 was prescribed for time period of two months . Urinanalysis, FBS, HbA1C and 24-hour urine protein levels were measured again after 2 months. Statistical Analysis The data was analyzed using descriptive statistical methods and reported as mean ± SD. Chi-square test was used to study qualitative variables. Mann-Whitney U-test was used for quantitative variables. Quantitative variables before and after treatment were statistically analyzed using Wilcoxon test. We used SPSS version 17.0 software. In this study p<0.05 was significant. Results In this study, 70 patients with type II diabetes mellitus, with mean age of 61.8±8.5 years were enrolled (the oldest and youngest patients were 78 and 40 years old, respectively). Thirty three patients were male (47.1%) and 37 (52.9%) were female (p=0.1). These patients randomly divided into two groups (each one had 35 patients). Case group (with mean age of 60.2 ±10.1 years) was treated with lozartan along with NAC and control group (mean age of 63.4±6.4 years) was treated just with losartan. Age difference was not significant (p=0.1). Initial mean FBS level before intervention was 174.9±41.1 in case and193.4±54.1 mg/dl in control group .Difference was not significant (p=0.1).HbA1c serum level was 8.6±1.6 in case and9.2±1.6 in control group. Difference was not significant statistically (p=0.09) so glycemic control was similar in both groups.Proteinuria has not remarkable difference in studied group (24-hours urine protein level was 1435.02±247.3 mg in case and 1027.6±367.9 mg in control group ) (p=0.7).Demographic characteristics of groups are presented in Table 1. Before Llosartan administration the mean level of proteinuria in control group was 1027.6±367.9 and after treatment with this drug protein excretion level was 417.2±121.1 mg/24h. Proteinuria decreased significantly after therapy (p=0.005). Before Losartan and NAC administration the mean level of proteinuria in case group was 1435±247.3 and after combination therapy it decreased to521.1±169.3 mg/24h. Proteinuria 5 diminished significantly in this group itself (p=0.05).Proteinuria level before therapy is seen in Figure 1. Comparison of proteinuria level in these two groups showed that difference is not significant (p=0.5) (Figure 2).It is clear that combination therapy was not more effective than Losartan alone in decreasing of proteinuria in our studied patients. Discussion It is estimated that more than 150 million people suffer from type II diabetes and its complications. Its prevalence will be double fold during the next 25 years (15). Diabetic nephropathy is manifested with complications including hypertension, micro and macroalbuminuria (proteinuria), renal function impairment, cardiovascular diseases and finally increasing of mortality and morbidity. Therefore, treatment or at least stabilization of above mentioned complications is essential (16). Proteinuria and microalbuminuria are well known risk factors for progression of persistant renal damage. For this reason, several therapeutic methods have been proposed to reduce them. Suppression of the renin-angiotensin-aldostrone (RAAS) system through inhibiting the converting enzyme or blocking of the angiotensin receptor is one of the most important therapeutic approaches (17).RAAS is also activated by sympathic nervous system. Noshad designed a study with combination therapy (Enalapril, Losartan and Metoral) for optimal control of RAAS activity. Results were remarkable, proteinuria decreased and glomerular filtration rate improved significantly (p=0.001, p=0.01 respectively) (26). Angiotensin receptor blocking is corner stone of all suggested therapeutic plans. Many different researchers like Zeeuew et al showed that treating with Lozartan in patients suffering from type II diabetes is really efficient and leads to considerable decreasing of albuminuria. Diminishing of albuminuria in a 6-month therapeutic period can be regarded as useful effects of RAAS control. This system- an independent risk factor predicting renal damages- is well suppressed by this drug (18). Viberti used 80 mg of valsartan per day and showed that albuminuria was decreased significantly (19). Also, Eijkelkamp in his study demonstrated that angiotensin receptor blocking drugs in a 6month follow-up period of diabetic patients decreased albuminuria in 51 percent of them (20).In a randomized clinical trial study, Rossing proved usefulness of angiotensin receptor blocking drugs in decreasing of albuminuria and proteinuria of patients with type II diabetes mellitus (21). In many metanalysis studies contrast nephropathy was prevented by NAC (30, 31). According to our randomized clinical trial study, treating with angiotensin receptor blocking drugs in control and angiotensin receptor blocking drugs along with N-acetyl cysteinein in case group for 6 eight weeks was effective in decreasing 24-hour urine protein level .But comparing these two form of therapies did not show any significant difference. So blocking of angiotensin receptor alone was as effective as Losartan+NAC. Angiotensin II and oxidative stress lead to progression of glumerolonephritis with producing NADPH oxidase (22). N-acetyl Cysteine (NAC) has useful effects on free radical and oxidative stress also it has additional vasodilation effects. Plasminogen inhibitors have important role in extracellular matrix fixing. Hyperglycemia promotes plasminogen inhibitors and induces free oxygen radicals. These phenomenons hurt the glomerular mesangial cells in diabetic patients. Lee studied protective effects of NAC in this condition (23). They showed that NAC reduces plasmingen inhibitors levels effectively and diminishes free oxygen radicals. They concluded that NAC was effective in molecular level but other clinical studies requested (23). Lee showed that N-acetyl Cysteine led to oxidative stress system (ROS) suppression and production of intermediate metabolites of free radical .It significantly decreases these agents in patients with greater blood glucose levels (23). Trend to using of NAC due to its anti Oxidative effects is increased (32). In animal models of Pieper ,antioxidants and NAC in mice ,48 hours after receiving streptozotocin successfully decreased proteinuria and function of endothelial cells preserved (24). Clinically, only one study has been done for demonstrating of N-acetyl Cysteine effect on proteinuria of diabetic patients (Saklayan et al) .This research revealed uselessness of the this drug in proteinuria of diabetic patients (25). According to the results of this study, there was no statistical difference in proteinuria before after and even during follow-up period of N-acetyl cysteine administration. However, some animal models and in vitro studies demonstrated useful effects of NAC in decreasing oxidative stress and regulating of kidney mesangial cells recovery. The results are opposite of this study. In our study effects of 8-weeks treatment with N-acetyl cysteine along with angiotensin receptor blocking drugs was evaluated in proteinuria of patients with type 2 diabetes mellitus. No significant difference was observed comparing with angiotensin receptor blocking drugs alone. Decreasing of proteinuria was almost as the same for both groups and adding of N-acetyl Cysteine had no extra advantage. This is opposite of animal models findings, but it is similar to Saklayen study (25). Diabetes mellitus is a chronic disease and because of long time exposure of glomerulus with higher levels of glucose, we suggest studies with longer time period and greater sample size for better 7 clarifying of NAC in diabetic patients.We did not measure the oxidative stress levels after NAC administration and we suggest measuring of these agents in future studies. Conclusion: As previous reports, results of the present study revealed that use of ARB in diabetic patients with proteinuria is more effective and useful in reducing protein excretion from kidney. Also, adding of N-acetyl Cysteine (NAC) did play no role in diabetic patients with proteinuria. Acknowledgments ……………….. 8 References: 1. Valmadrid CT, Klein R, Moss SE, Klein BE. The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med (2000), 160, 1093–1100. 2. Mogensen Ce, Christensen CK.. 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Arterial atherosclerosis in patients with chronic kidney disease and its relationship with serum and tissue endothelin-1, Iran J Kidney Dis. 2009 ;3(4):203-9. 27. Rippin J, Bain SC, Barnett AH. Rationale and design of diabetics exposed to telmisartan and enalapril (DETAIL) study. J Diabetes Complications 2002;16:195-200. 11 28. Parving HH, Lehnert H, Bröchner- Mortensen J, et al.The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. (2001),345,870-8. 29. Deray G.Value of N-acetylcysteine to prevent nephrotoxicity from iodinated contrast agents, J Radiol. 2004; 85(6 Pt 1):725-7. 30.Birck R, Krzossok S, Markowetz F, Schnulle P, van der Woude FJ, Braun C. Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet, (2003) 362,598-603. 31.Misra D, Leibowitz K, Gowda RM, Shapiro M, Khan IA. Role of N-acetylcysteine in prevention of contrastinduced nephropathy after cardiovascular procedures: a meta-analysis. Clin Cardiol(2004),27,607-610. 32. Ng TM, Shurmur SW, Silver M, Nissen LR,,et al. (2006) Comparison of N-acetylcysteine and fenoldopam for preventing contrast-induced nephropathy (CAFCIN). International Journal of Cardiology, 109, 322–328. 12 Table 1: Demographic characteristics and laboratory measurement between two groups. Case Control N=35 N=35 Age(years) 60.2±10.1 63.4±6.4 0.1 Sex(Male/Female) 19/16 20/15 0.08 FBS(mg/dl) 174.9±41.1 193.4±54.1 0.1 HbA1c(%) 8.6±1.6 9.2±1.6 0.09 Proteinuria(mg/24 h) 1435.02±247.3 1027.6±367.9 0.7 Variable p 13 Figure 1: Proteinuria before therapy between two groups. 14 Figure 2: Proteinuria after therapy between two groups. 15