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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
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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.
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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).
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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
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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
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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
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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
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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
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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.. Predicting diabetic nephropathy in insulin-dependent patients. N
Engl J Med 1984; 311: 89-93.
3. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme
inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993 Nov
11;329(20):1456-62.
4. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli
P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic
renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal
Insufficiency Study Group. N Engl J Med. 1996 Apr 11;334(15):939-45.
5. The GISEN GroupRandomised placebo-controlled trial of effect of ramipril on decline in
glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy.
Lancet.(1997);349,1857-63.
6. Brown NJ, Vaughan DE. Angiotensin converting enzyme inhibitors.Circulation(1998),97,1411-20.
7. Stevens M, McCullough P, Tobin K, et al. A prospective randomized trial of prevention measures
in patients at high risk for contrast nephropathy. J Am Coll Cardiol(1999),33,403– 11.
8. Gare M, Haviv Y, Ben-Yehuda A, et al. The renal effect of low-dose dopamine in high-risk
patients undergoing coronary angiography. J Am Coll Cardio(1999)l,34,1682– 8.
9. Hall K, Wong R, Hunter G, et al. Contrast-induced nephrotoxicity: the effects of vasodilator
therapy. J Surg Re(1992)s,53,317– 20.
9
10. Solomon R, Werner C, Mann D, D’Elia J, Silva P. Effects of saline, mannitol,and furosemide on
acute decreases in renal function induced by radiocontrast agents. N Engl J Med(1994),331,1416–
20.
11. Seyss C, Foote E. Calcium-channel blockers for prophylaxis of radiocontrastassociated
nephrotoxicity. Ann Pharmacother(1995),29,187–8.
12. Abizaid A, Clark C, Mintz G, et al. Effects of dopamine and aminophylline on contrast-induced
acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency. Am J
Cardiol(1999),83,260–3.
13. Conesa E, Valero F, Nadal J, et al. N-acetyl-l-cysteine improves renal medullary hypoperfusion
in acute renal failure. Am J Physiol Regul Integr Comp Physiol. (2001)281,730–7.
14. DiMari J, Megyesi J, Udvarhelyi N, Price P, Davis R, Safirstein R.Nacetylcysteine ameliorates
ischemic renal failure. Am J Physiol, (1997) 272,292–8.
15. Amos A, Mccarty D, Zimmet P. The rising global burden of diabetes and its complications:
Estimates and projections to the year 2010. DiabetesMed(1997), 14,1–85.
16. AMERICAN DIABETES ASSOCIATION. Management of dyslipidemia in adults with diabetes.
Diabetes Care(2003) 26 1,83–86.
17. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression
of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med(2001),
135(2),73–87.
18. de Zeeuw D, Remuzzi G, Parving H, et al. Proteinuria, a target for renoprotection in patients with
type 2 diabetic nephropathy: Lessons from RENAAL. Kidney International (2004), 65, 2309–2320.
19. Viberti G, Wheeldon M . Microalbuminuria Reduction With Valsartan in Patients With Type 2
Diabetes Mellitus A Blood Pressure–Independent Effect. Circulation; (2002)106;672-678
10
20. Eijkelkamp W B. Zhang Z, Remuzzi G, et al. Albuminuria is a Target for renoprotective therapy
independent from blood pressure in patients with type 2 Diabetic Nephropathy: Post Hoc Analysis
from the reduction of endpoints in NIDDM with the Angiotensin II antagonist Losartan (RENAAL)
Trial. J Am Soc Nephrol ( 2007) 18,1540–1546.
21. Rossing K, Jacobsen P, Pietraszek L, Parving HH. Renoprotective effects of adding Angiotensin
II receptor blocker to maximal recommended doses of ACE Inhibitor in diabetic nephropathy.
Diabetes Care(2003), 26,2268–2274.
22. Kondo S, Shimizu M, Urushihara M, et al. Addition of the Antioxidant Probucol to Angiotensin
II Type I Receptor Antagonist Arrests Progressive Mesangioproliferative Glomerulonephritis in the
Rat. J Am Soc Nephrol(2006) 17, 783-794.
23. Lee EA, Seo JY, Jiang Z, Yu MR, et al. Reactive oxygen species mediate high glucose-induced
plasminogen activator inhibitor- 1 up-regulation in mesangial cells and in diabetic kidney. Kidney
Int(2005),67(5),1762-71.
24. Pieper GM, Siebeneich W. Oral Administration of the Antioxidant, N-Acetylcysteine, Abrogates
Diabetes-Induced Endothelial Dysfunction. Journal of Cardiovascular Pharmacology, (1998)32 (1 ),
101- 105.
25. Saklayen MG, Yap J, Vallyathan V. Effect of month-long treatment with oral N-acetylcysteine
on the oxidative stress and proteinuria in patients with diabetic nephropathy: a pilot study. J Investig
Med. (2010),58(1):28-31.
26. Noshad H, Argani H, Nezami N, Ghojazadeh M, et al. 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.
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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
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Figure 1: Proteinuria before therapy between two groups.
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Figure 2: Proteinuria after therapy between two groups.
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