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Raa Blocade
Raa Blocade
Raa Blocade
Keywords
Dual blockade; Long-term effect;
Reninangiotensin system.
Correspondence
Roberto Robles, M.D., Ph.D.,
Nicolas
Servicio de Nefrologia, Hospital Infanta Cristina,
Carretera de Portugal s/n. 06080, Badajoz,
Spain.
Tel./Fax: +34924218117;
E-mail: nroblesp@senefro.org
doi: 10.1111/j.1755-5922.2009.00084.x
Introduction
A proportion of patients show secondary increases in angiotensin II and aldosterone concentrations after longterm use of ACE inhibitors. [1] Also, angiotensin II receptor blocker (ARB) treatment results in rebound increases in systemic concentrations of renin and angiotensin II by interrupting negative feedback within the
reninangiotensin system (RAS). [2,3] Because of these
shortcomings of single therapies, many investigators are
examined whether dual blockade of the RAS by combination treatment with an ACE inhibitors and an ARB
may offer more complete blockade of the RAS. So that,
dual blockade of RAS has been tested in the treatment
of renal disease associated to micro or macroalbuminuria, in congestive heart failure and also after myocardial
infarction. Several authors have reported a superior effect of the combination of ACE inhibition and ARB on
microalbuminuria and on clinical proteinuria in patients
with primary nephropathies [46] and in type 1 and type
2 diabetic patients. [7,8] A systematic review and metaanalysis has addressed this issue suggesting that concomitant therapy with an ARB and an ACE inhibitor leads to
greater reductions in proteinuria than monotherapy. [9]
Moreover, dual RAS blockade safety retards progression
of nondiabetic renal disease compared with either ACE
inhibitor or ARB monotherapy. [10]
Nevertheless, most of the published trials have had
very short follow up times; usually less than 12 weeks.
[49, 1123] Only the COOPERATE trial [7] have an extended follow-up period (near 3 years). Most recently
the long term renal results of ONTARGET trial has been
101
102
Gender
Causes of proteinuria
Diabetic nephropathy
Idiopathic chronic
glomerulonephritis
Interstitial nephritis
Hypertensive nephropathy
Hyperltration
glomerulopathy on single
functioning kidney
Alport disease
Results
Proteinuria was significantly reduced in each visit after
combined treatment (see Table 2) and the effect remains
after 36 months of follow up (baseline, 2.94 1.92 g/24
h; 36th month, 2.35 3.1, P = 0.02, Wilcoxon test)
(Fig. 1). Mean reduction at last visit was 14.1%. Changes
in plasmatic total proteins and albumin were not significant.
No significant reduction of DBP was observed throughout the study. Differences on SBP were only significant
at 12 month (baseline, 136.5 20.1 mmHg; 12th month,
130.9 18 mmHg, P = 0.04, Student t test). The changes
of blood pressure are shown in Table 3 and figure 2.
Mean K+ was significantly increased in every visit, but
it was not a steady increase but the kaliemia tends to be
stable after the second (6 month) visit (values are shown
in Table 4). Averaged plasmatic creatinine levels were
ACE inhibitor
Dose
ARB
Dose
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Trandolapril
Quinapril
Quinapril
Ramipril
Enalapril
Trandolapril
Trandolapril
Ramipril
Enalapril
Moexipril
Perindopril
Perindopril
Perindopril
Enalapril
Quinapril
Quinapril
Enalapril
Enalapril
Enalapril
Enalapril
Perindopril
Quinapril
Enalapril
Ramipril
Enalapril
Perindopril
Perindopril
Perindopril
2
20
40
5
20
2
2
5
10
6
4
4
4
20
10
20
20
5
20
20
4
40
20
2.5
20
4
4
4
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
Candesartan
8
16
8
8
16
16
32
16
16
16
16
16
16
32
32
16
16
8
16
16
16
8
16
8
16
32
32
16
Doses in mg/24 h.
Discussion
Experimental studies suggest that proteinuria is not only
a predictor of renal outcome, but also acts as a pathogenic
factor for the progression of renal disease, at least within
the proteinuric range. [29] Recent post hoc data suggest a
linear relationship between reduction in urinary protein
excretion and protection of renal function. [30] So that
proteinuria seems to be a reliable surrogate marker of renal disease progression and the additional reduction in
proteinuria achieved by combining an ARB and an ACE
inhibitor may be of direct relevance to the patients renal prognosis. The benefit of dual blockade of the RAS in
human kidney disease was first demonstrated by Zoccali
et al. [31] Since then, the combination of an ACE inhibitor and an ARB has been repeatedly tested in chronic
kidney disease, seeking an antiproteinuric effect beyond
that seen with a single agent. [121,32] The effect of dual
RAS blockade on protein excretion has been explored
in a number of studies. For example, in a study of normotensive patients with biopsy-proven IgA nephropathy
and nonnephrotic range proteinuria, the combination of
losartan and an ACE inhibitor produced a 73% reduction
in protein excretion (ACE inhibitor, 38%; losartan, 30%).
In this study, no further decrease in proteinuria was seen
after doubling the dose of either agent. [1] In this way,
we showed again that combination therapy of an ARB
and an ACE inhibitor provided more antiproteinuric efficacy than that observed with a dose of ACE inhibitor
alone.
The potential benefit of dual RAS blockade results from
the differing mechanisms of action of the two classes of
drugs on the RAS. ACE inhibitors exert their pharmacological effects by inhibiting the formation of angiotensin
II by ACE; their primary shortcoming is that they cannot prevent the production of angiotensin II via ACEindependent pathways. [33] Moreover chymase, an important source of angiotensin II, seems to be markedly
up regulated in diabetic and hypertensive nephropathy
103
Proteinuria
SBP
DBP
2.95 1.91
136.5 20.1
75.2 8.7
2.21 1.99
132.0 19.4
74.9 8.8
6
a
12
2.18 2.29
133.1 18.5
75.1 9.6
a
24
2.53 2.56
130.9 18.0b
73.8 9.6
36
2.35 3.01
133.5 25.9
73.4 7.3
Units
2.21 2.20
133.4 23.7
72.9 6.2
g/24 h
mmHg
mmHg
P < 0.01 vs. baseline. b P < 0.05 from baseline. Other differences are not signicant.
12
24
36
Units
K+
Creatinine
Cr clearance
Total proteins
Albumin
4.78 0.50
1.76 0.67
62.0 31.9
7.01 0.56
4.10 0.35
5.07 0.71a
1.84 0.74
56.0 33.0
6.95 0.83
4.18 0.41
4.94 0.63b
1.86 0.76a
63.1 42.6
7.00 0.50
4.16 0.44
4.94 0.55b
1.93 0.90a
63.0 39.1
6.92 0.66
4.13 0.39
5.16 0.54a
2.11 1.06b
54.7 38.3a
6.86 0.58
4.19 0.42
mmol/l
mg/dL
mL/min
g/24 h
g/24 h
P < 0.01 vs. 0 month. b P < 0.05 vs. 0 month. Other differences are not signicant. Cr clearance = creatinine clearance.
Table 5 Comparison between CRF group and normal renal function patients
Month
12
24
36
Units
K + CRF
K + NF
Cp CRF
Cp NF
CrC CRF
CrC NF
4.87 0.87
4.59 0.11
2.01 0.46
0.92 0.23
48.7 19.0
95.1 34.5
5.30 0.71
4.56 0.37
2.21 0.51
0.94 0.23
41.1 17.7
91.2 34.9
5.03 0.71
4.72 0.35
2.25 0.52
0.96 0.28
44.0 18.1
108.4 50.7
5.07 0.60
4.67 0.31
2.41 0.68
0.93 0.27
41.2 17.1
109.6 30.5
5.27 0.52
4.80 0.53
2.59 0.91
1.08 0.41
39.7 19.0
86.7 50.0
mmol/l
mmol/l
mg/dL
mg/dL
mL/min
mL/min
CRF = chronic renal failure; NF = normal function. P < 0.01 in every visit between both groups (ANOVA).
104
The ONTARGET study suggests an increased rate of renal failure among the patients studied but the populations studied are very different. Most of renal patients included in our study have high blood pressure and heavy
proteinuric renal disease due to diabetic nephropathy or
chronic glomerular disease. In the other hand, the patients recruited in ONTARGET were selected due to high
cardiovascular risk and most of then were included due
to ischemic coronary disease nonrelated to kidney disease. The have low blood pressure; this is the reason why
hypotensive problems were so frequent. Also they were
older and, as its antecedents suggest, they likely have renal microvascular nonproteinuric disease highly sensitive
to changes in blood pressure levels. [14] The characteristics of both populations are clearly noncomparable. Thus,
there is not reason to change the current management of
proteinuria in renal disease patients using dual blockade
of the reninangiotensin system whenever blood pressure is controlled and there is no complete response to
either ACE inhibitors or ABR alone. This therapy seems to
be useful and secure in most patients even in the stage III
of KDOQI Guidelines. Its use in patients with more severe
renal chronic failure need not be avoided but it should be
closely monitored. [39]
In conclusion, antiproteinuric effect of dual renin
angiotensin system blockade combining candesartan and
ACE inhibitors remain after 36 months without losing its
initial effect. Blood pressure changes seem not to completely explain this long-term antiproteinuric effect.
Conict of Interest
The authors have no conflict of interest.
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