Download irbesartan decreases microalbuminuria in patients with type ii

TJIC Volume:11 Number:1 February 2007
TGKD Cilt:11 Sayý:1Þubat 2007
IRBESARTAN DECREASES MICROALBUMINURIA IN PATIENTS
WITH TYPE II DIABETES MELLITUS FOLLOWING CORONARY
ARTERY BYPASS GRAFTING
Halil Ýbrahim Uçar, MD1, Mustafa Tok, MD1, Ömer Faruk Doðan, MD1, Barýþ Durukan, MD1, Alper
Gürbüz, MD1, Enver Atalar, MD2, Cevdet Furat, MD1, Bora Farsak, MD1, Murat Guvener, MD1,
Ali Cem Yorgancýoðlu, MD1, Rýza Doðan, MD1, Metin Demircin, MD1, Ilhan Paþaoðlu, MD1
Department of Cardiovascular Surgery, Hacettepe University, Faculty of Medicine, 2Department
of Cardiology, Hacettepe University, Faculty of Medicine, Ankara
1
Mikroalbüminüri artmýþ kapiller geçirgenliðin
buna baðlý olarak da özellikle böbrek fonksiyon
bozukluðu ve koroner arter bypass cerrahisi sonrasý ortaya çýkan sistemik inflamatuvar yanýtýn
önemli bir göstergesidir. Bu çalýþmada bir
angiotensin reseptör blokörü (ARB) olan irbesartanýn, koroner arter bypass cerrahisi yapýlan tip II
diabetik hastalarda mikroalbüminüri üzerindeki
etkisinin araþtýrýlmasý amaçlandý.
Tip II diabeti olan ve elektif koroner arter
bypass cerrahisi yapýlan 40 hasta çalýþmaya dahil
edildi. Hastalar kullandýklarý ilaca ek olarak en az 6
aydýr günlük 300 mg irbesartan kullananlar (grup I)
ve ARB kullanmayanlar (grup II) olmak üzere iki
gruba ayrýldý. Hastalardan dört ayrý zaman diliminde idrar örnekleri toplanarak Micral-test çubuklarý ile mikroalbüminüri ölçümleri yapýldý.
Preoperatif, postoperatif 1. saat, postoperatif
1.gün (POD 1) ve postoperatif 5.gün (POD 5)
mikroalbüminüri seviyelerine bakýldý. Grup I'de
mikroalbüminüri seviyeleri sýrasýyla 16.5±17.2
mg/l, 28.5±17.2 mg/l, 59.0 ± 29.8 mg/l, 23.0±20.0
mg/l, ve grup II'de 30.0±17.7 mg/l, 51.0±28.4 mg/l,
75.0 ± 25.6 mg/l, 52.5 ± 27.5 mg/l olarak ölçüldü. Ýki
INTRODUCTION
Microalbuminuria has long been considered as a
marker of early nephropathy and an independent,
strong predictor of increased risk for cardiovascular
mortality and morbidity in both diabetic and non-diabetic patients1,2. Proteinuria is also an early marker for
Corresponding Author: Halil Ibrahim Ucar, MD
Duygulu S. No: 45/4 Aydinlikevler
06130 Ankara / Turkey
Tel: +90 312 305 17 74
Fax: +90 312 311 73 77
e-mail: [email protected]
grup arasýnda preoperatif, postoperatif birinci
saat ve POD 5.gün deðerleri istatistiksel olarak
anlamlý bulundu (sýrasýyla, p = 0.018, p = 0.008, ve
p = 0.001). Bununla birlikte POD 1.gün deðerleri
gruplar arasýnda anlamlý olmaya yakýn olarak
bulundu (p = 0.071). Gruplar arasinda preoperatif
high
sensitif
C-reaktif
protein
(hsCRP)
seviyelerinde (0.35±0.17 mg/l vs 0.5±0.32 mg/l)
anlamlý olmaya eðilim gözlendi (p = 0.069). POD 1.
gün deðerleri (10.0±2.0 mg/l vs 17.8±3.9 mg/l) istatistiksel olarak anlamlý deðildi (p = 0.405), bununla
birlikte grup I'de POD 5. gün hsCRP deðerlerindeki azalma (8.6±2.9 mg/l vs 10.9±3.2 mg/l) istatistiksel olarak anlamlý bulundu (p = 0.024).
Ýrbesartan, bir AII reseptör blokörü olarak
koroner arter bypass cerrahisi yapýlan tip II diabetik hastalarda mikroalbüminürünin azaltýlmasýnda önemli bir rol oynamaktadýr.
Anahtar sözcükler: Koroner arter cerrahisi,
Mikroalbüminüri, Ýrbesartan, Koroner arter
hastalýðý
(Türk Giriþimsel Kard. Der. 2007;11: 1-6)
potentially serious renal disease in diabetics3-5. In addition, it refers to an abnormally increased excretion rate
of albumin in the urine and a sensitive index of generalized microvascular disease and a marker for vascular endothelial injury and multiorgan damage1-4. Proteinuria also contributes to renal scarring, and accelerates the progression of chronic kidney disease to endstage renal failure. Reduction of microalbuminuria in
diabetics may retard its progression to overt diabetic
nephropathy5. On the other side, it is well known that
2
Uçar ve ark.
Irbesartan and microalbuminuria after CABG
cardiac surgery with cardiopulmonary bypass (CPB)
cause a systemic inflammatory response, which can
lead to end-organ dysfunction with postoperative
mortality and morbidity. Most of the sequelae result
from CPB, and are often accompanied by increased
capillary permeability6. Microalbuminuria is one of the
main predictors as a sensitive sign of increased capillary permeability and thus might be a useful predictor to asses the systemic inflammatory response,
especially renal dysfunction, after coronary artery
bypass grafting (CABG)6.
Once microalbuminuria is present, the rate of
progression to end stage renal disease and of cardiovascular disease can be delayed by aggressive
management. Inhibition of the renin-angiotensin system is important to reduce intraglomerular pressure7.
Agents that block the renin-angiotensin-aldosterone
system (RAAS), notably angiotensin receptor blockers (ARBs), reduce proteinuria and microalbuminuria, lower blood pressure and slow the progression
of proteinuric kidney disease8. Irbesartan is an
angiotensin II (AII) receptor antagonist, effectively
blocking the renin-angiotensin system8. We conducted a study to investigate the effects of the selective
angiotensin receptor I antagonist, irbesartan, on the
microalbuminuria after coronary artery bypass
surgery in patients with diabetes mellitus.
METHODS
Preoperative evaluation: The study was approved
by the local Ethics Committee. Informed consent was
obtained from all participants. This clinical trial was
conducted in accordance with the amended Declaration of Helsinki and Good Clinical Practice regulations. A total of 40 patients with a mean age of
65.0±8.6 (range, 40 to 79 years) who had type II diabetes mellitus were enrolled in this study. Patients
were divided into two groups regarding preoperative
angiotensin receptor blocking agent, irbesartan
(Karvea, Sanofi-Aventis, Istanbul, Turkey). Fourty
patients (29 male; % 72.5 and 11 female; % 27.5)
were enrolled into two groups.
Group I included 20 patients with a mean age of
65.6±7.8 years who were using irbesartan 300 mg
daily for at least 6 months. Group II included 20
patients with a mean age of 64.4±9.5 years who used
no angiotensin receptor blocking agent prior to the
operation. In both group no patients were using
angiotensin converting enzyme inhibitors for at least
6 months.
Smoking, obesity, hypertension, duration of diabetes, family history of coronary artery disease,
preoperative myocardial infarction (MI), preoperative
hemodynamic data were recorded. We excluded
patients with severely impaired left ventricular func-
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tion, chronic pulmonary obstructive disease, severe
systemic noncardiac disease, severe renal or liver
impairment, infectious disease before operation,
malignancy, and those receiving corticosteroid or
other immunosuppressive treatment. We also
excluded patients with stroke or acute coronary
syndrome, inflammatory disease, and/or surgery,
and valvular heart disease. Cardiac medication,
including beta-adrenergic blocking agents, calciumchannel blocking agents, and nitrates, was continued
until the morning of surgery.
Operative technique and anesthesia: The same
general anesthetic drugs were used in all patients.
Standard median sternotomy incision was used for
the exposure of the heart and placement of the internal mammary artery and saphenous vein grafts were
used for coronary anastomosis. In each group, routine operations were performed using a membrane
oxygenator (Edwards Vital, Edwards Lifesciences
LLC, Irvine, CA, USA), a 3 mg/kg dose of heparin
sodium, 2000 mL of Ringer's lactate priming, a roller
pump, a body temperature of 28°C were used. Cardiopulmonary bypass was instituted via the ascending aorta and single two stage venous cannulation
(maintained at 2.2 to 2.4 liter/min-1 per m-2). Following cross-clamping of the aorta, the heart was
arrested by using 10-15 cc/kg cold blood cardioplegia
through the aortic root and topical ice slush, continued with in every 20 minutes for myocardial protection. Heparin was neutralized with protamine
hydrochloride (Protamin 1000; Roche, Istanbul,
Turkey). The circuit was primed with 2000 mL.
Hemodynamic parameters, including heart rate,
mean arterial pressure, central venous pressure,
arterial blood gases and urine output were monitored
throughout the procedure. After completion of
surgery, patients were transferred to the intensive
care unit (ICU), where standard care and processes
were followed until discharge. Patients were weaned
from mechanical ventilation when they were hemodynamically stable, responded to verbal stimulation,
were completely rewarmed, and when blood loss did
not exceed 100 mL/h-1. Cardiovascular and respiratory values and temperature were recorded every 15
minutes before extubation and then hourly until
discharge from the ICU. Length of stay in the ICU
was also recorded. Patients were discharged from
the ICU if they were hemodynamically stable, had
normal blood gases during spontaneous breathing,
and had satisfactory renal function.
Operative and postoperative evaluation: All CABG
operations were performed successfully. There were
no repeated surgery for bleeding and perioperative
MI in both groups. The following complications were
observed: cerebrovascular accident (n = 1) in group
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Uçar ve ark.
Irbesartan and microalbuminuria after CABG
Table 1: Patients clinical characteristics
Group I (irbesartan +)
Age (year)
Gender (M/F)
Smoking
History of MI
Body mass index
Hypertension
Hyperlipidemia
Total patient (n)
65.6±7.8
15/5
11 (55 %)
12 (60%)
28.0±4.7
18 (90%)
19 (95%)
20
Group II (irbesartan -)
64.4±9.5
14/6
10 (50 %)
13 (65%)
26.5±2.8
16 (80%)
18 (90%)
20
p value
0.680
0.723
0.752
0.744
0.234
0.661
1.000
(M/F: Male / Female), MI: Myocard Infarction
Table 2: Operative and postoperative features of the patients
Group I (irbesartan +)
Bypass number
Cardiopulmonary bypass time (min)
Xclamp time (min)
Flow (cc)
Atrial fibrillation
Inotrop usage
Mortality (n)
Total patient (n)
2.9±1.0
87.4±31.3
52.6±21.6
4469.0±362.4
4 (20%)
3 (15%)
20
II. There was no clinical or laboratory evidence of
postoperative renal dysfunction in either group. Urine
output during surgery and in the postoperative period
did not differ between the groups.
Operative and early postoperative (in ICU) blood
glucose levels were controlled by insulin infusion if
necessary for all patients; serum creatinine and
blood urea nitrogen (BUN) were studied on the postoperative day (POD) 1, 2, 3 and 5. Patients who
were considered to be in low cardiac output (LCO)
state, and received positive inotropic agents
(dopamine or adrenaline or both) were assessed by
persistent systemic pressure below 90 mmHg, urinary output lower than 20 cc/h, and the state of
peripheral circulation in the presence of adequate
preload and optimal afterload. Four intervals of urine
samples were obtained and measured for microalbuminuria using Micral-test sticks (Roche). No wound
infection was observed for each patient.
Statistical analysis: Categorical variables were
analyzed with Chi-square and Fisher's exact tests as
appropriate in contingency tables whereas Student's
t-test and Mann-Whitney U-test were performed as
appropriate for comparison of continuous variables.
Comparision for microalbuminuria and hsCRP in the
group were done with the Repeated measures of
ANOVA and Bonferroni test. Data were expressed as
means ± the standard deviation. A p value less than
Group II (irbesartan -)
2.9±0.9
86.6±20.4
53.2±18.5
4491.0±295.0
6 (30%)
6 (30%)
2 (10 %)
20
p value
0.876
0.920
0.925
0.834
0.716
0.451
0.487
0.05 was considered as statistically significant. All
statistical analyzes were performed with the Statistical Package for Social Sciences (SPSS 10.0 for Windows, SPSS, Inc., Chicago, IL).
RESULTS
Two groups did not show significant differences
and were comparable with respect to clinical characteristics (Table 1).The groups also did not show any
significant differences with respect to bypass number, cardiopulmonary bypass time, X-clamp time,
flow, atrial fibrillation, inotrop usage, time of
endotracheal intubation and mortality (Table 2).
Preoperative, postoperative 1st hour, POD 1 and
POD 5 microalbuminuria levels were 16.5±17.2 mg/l,
28.5±17.2 mg/l, 59.0±29.8 mg/l, 23.0±20.0 mg/l in
group I, and 30.0±17.7 mg/l, 51.0±28.4 mg/l,
75.0±25.6 mg/l, 52.5±27.5 mg/l in group II, respectively and there were statistically significant difference between four microalbuminiria levels for each
group (p < 0.001) (Table 3). Preoperative, postoperative 1st hour and POD 5 values were statistically
significant between the groups (p = 0.018, p = 0.008,
and 0.001 respectively) (Table 3). However, the difference of POD 1 values between the groups were at
the threshold of significancy (p = 0.071). Preoperative plasma levels of hsCRP (0.35±0.17 mg/l vs
0.50±0.32 mg/l) showed a trend towards significancy
3
4
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Irbesartan and microalbuminuria after CABG
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Table 3: Microalbuminuria levels
Microalbuminiria level (mean±SD)
Group I
Group II
p
Postoperative 1st hour
28.5±17.2**
51.0±28.4**
0.008
Preoperative
16.5±17.2*
30.0±17.7*
0.018
POD1
59.0±29.8***
75.0±25.6***
0.071
POD5
23.0±20.0****
52.5±27.5****
0.001
p
< 0.001
< 0.001
POD 1:Postoperative 1st day, POD 5: Postoperative 5th day
Group I: * vs ***:
* vs ****:
** vs ***:
*** vs ****:
p
p
p
p
<
=
=
=
0.001
0.036
0.021
0.036
Group II: *vs *** :
** vs *** :
** vs **** :
*** vs **** :
p < 0.001
p < 0.001
p < 0.001
p < 0.001
Table 4: High sensitive CRP levels
Group I (irbesartan +)
Preoperative sensitive CRP (mg/l)
First day hsCRP (mg/l)
Fifth day hsCRP (mg/l)
Total patient (n)
0.35±0.17
17.0±2.0
8.6±2.9
20
Group II (irbesartan -)
0.5±0.32
17.8±3.9
10.9±3.2
20
p value
0.069
0.405
0.024*
hsCRP: High sensitive C-reactive protein (hsCRP levels were statistically significant in the groups at the level of p <
0.001). * indicates the statistical significant difference.
(p = 0.069). Although POD 1 hsCRP levels (10.0±2.0
mg/l vs 17.8±3.9 mg/l) did not differ (p = 0.405),
decrease in POD 5 hsCRP levels in group I (8.6±2.9
mg/l vs 10.9±3.2 mg/l) was statistically significant
between the groups (p = 0.024) (Table 4).
DISCUSSION
Coronary artery bypass grafting is often followed
by a systemic inflammatory response. The clinical
relevance of CPB related systemic inflammation
varies with the patient and such inflammation may be
accompanied by intermittent organ dysfunction and
finally multi-organ failure including renal and pulmonary functions9. In some patient groups, the
effects of extracorporeal circulation (ECC) is very
important after the open heart surgery and it is well
known that diabetic cases are frequently associated
with renal and cardiovascular disease requiring surgical and medical intensive care. Some pathophysiologic mechanisms such as microalbumiuria and urinary protein over- excretion are responsible for these
damaging effects in this particular group.
In patients with diabetes, AII is believed to play a
main role in the progression of renal damage not only
through hemodynamic effects but also non-hemodynamic effects, including stimulation of growth factors
and cytokines and alterations in extracellular matrix
metabolism10-11. AII gives rise to glomerular hypertension and can alter the filtration properties of the
glomerular basement membrane, leading to
proteinuria12-13. Angiotensin II antagonists (AIIAs) may
block AII's growth-promoting, profibrotic, non-hemodynamic effects, and this too may contribute to the
observed renoprotection. AIIAs have been shown to
consistently produce favorable mortality and morbidity outcomes in endpoint trials in patients with type
2 diabetes and diabetic nephropathy14-16.
Microalbuminuria refers to the increased excretion of albumin into the urine, which is so slight that it
can be detected only by sensitive immunologic analysis technique. Microalbuminuria is measured in diabetic patients to predict incipient nephropathy. The
predictive value of microalbuminuria for the expression of cardiovascular diseases has also been investigated and, in fact, is as powerful as for hyperlipidemia or hypertension17.
Microalbuminuria also occurs in acute conditions,
where capillary permeability increases. Microalbuminuria increases during major surgery such as
CABG and ECC activates an inflammatory cascade,
which might increase capillary permeability and
cause microalbuminuria. The increase in capillary
permeability might induce lung exudation of proteins
from capillaries into the capillary-alveolar interspace
and alveoli, causing socalled postperfusion lung,
which resembles pulmonary edema.
We found that Irbesartan, as an ARB agent, had
a significant decreasing effect on microalbuminuria in
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type 2 diabetic patients undergoing coronary bypass
surgery in our study. A significant decrease in hsCRP
levels in day 5 between the groups. As several previous studies showed that ARB's are effective antiinflammatory agents, our patients receiving irbesartan revealed decreased levels of systemic inflammation after CABG. This anti-inflammatory effect of irbesartan may help to preserve postoperative renal functions and also vascular endothelial functions that
might be seen after bypass surgery as well.
As we know that renal dysfunction is a serious
complication of coronary revascularization with CPB
and results in increased morbidity, mortality, and prolonged hospital stay18. The injurious action of CPB on
renal function is caused by several mechanisms,
including nonpulsatile perfusion and increased levels
of circulating catecholamines, cytokines, and free
hemoglobin19. These effects result in damage to
glomerular as well as tubular structures that, in turn,
can produce renal dysfunction especially in the
presence of additional risk factors20-21.
Microalbuminuria is one of the sensitive signs of
increased capillary permeability and thus might be
useful to study the systemic inflammatory response,
especially renal dysfunction, after CABG6,22. According to the previous investigations, we also detected
urinary microalbuminuria increased significantly in the
early postoperative period in our cases22-24 and first
day after CPB peak microalbuminuria increase was
observed in both groups but there was no statistically significance (p = 0.071). These levels decreased
especially in the 5th day in our cases. However, the
decrement of the microalbuminuria was statistically
significant in those administrated ARB agent. In both
groups, hsCRP increased and rose the peak level in
the first day after operation in both groups. But, in the
study group, hsCRP as a one the proinflammatory
agents decreased significantly in 5th day in ARB
group. Therefore, the increment of the acute inflammatory response was not differ in both groups in the
first postoperative day, in ARB group, the both markers have decreased in 5th day.
Johnsen et al. and Yorgancioglu et al. showed the
direct relation of proteinuria and cardiovascular mortality in insulin-dependent diabetic patients after open
heart surgery in patients undergoing CABG1,25. Irbesartan was also shown to reduce or normalize
microalbuminuria in 34% of patients with diabetes
and developing renal dysfunction in a second,
smaller study including 64 hypertensive and 60 normotensive patients, confirming that irbesartan
reduces microalbuminuria independently of its blood
pressure lowering effects. Restoration of normal urine
albumin levels has also been demonstrated by irbe-
Uçar ve ark.
Irbesartan and microalbuminuria after CABG
5
sartan26-27.
Indeed, our study showed that irbesartan reduces
microalbuminuria not only preoperatively but also
reduces after open heart surgery. The return to the
baseline levels was also faster than Group II (Graphic 1). ARB agents decrease the some of the postoperative acute inflammatory agents in on-pump
CABG patients with diabetes mellitus by lessening
the systemic consequences of renal dysfunction and
may have additional cardiovascular effects by exerting beneficial effects on endothelial elsewhere in the
body and within the heart in this patients group. The
cardiovascular benefits of AIIAs have been evaluated
not only in terms of their ability to lower blood pressure but also on their ability to prevent strokes, cardiac events, and target organ damage14,16,28.
In conclusion, our results showed that irbesartan
decreased systemic inflammation and decreased urinary albumin excreasion compared to patients not
taking an ARB in diabetic patients after CABG
surgery. These beneficial effects of irbesartan treatment on diabetic patients after CABG should be
investigate further prospective and randomized studies.
Acknowledgement: The authors would like thanks to
Associate Prof. Dr. Murat Kara and Dr. Elif Durukan
for supporting of the statistical analyses.
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