RESEARCH

Long-Term Antiproteinuric Effect of Dual ReninAngiotensin

System Blockade
N.R. Robles, E. Fernandez Carbonero, B. Romero, E. Sanchez
Casado & J.J. Cubero

Servicio de Nefrologa, Hospital Infanta Cristina, Badajoz, Spain

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

We evaluated the long-term changes on overt proteinuria induced by dual

blockade of the reninangiotensin system (RAS). Dual blockade was produced
by adding an angiotensin II receptor blocker (ARB) to treatment with maximal
recommended doses of an angiotensin converting enzyme (ACE) inhibitor in
proteinuric patients. A total of 28 patients (19 men and 9 women) with proteinuria higher than 1 g/24 h were enrolled in this trial of treatment with the
ARB candesartan (from 4 up to 32 mg daily) added to existing treatment with
an ACE inhibitor. At 6, 12, 24, and 36 months, we evaluated proteinuria in
24-h urinary collections, office blood pressure (BP), plasmatic creatinine (Cr),
serum potassium (K), and 24 h urine collection creatinine clearance (CrC).
During monoblockade of the RAS by ACE inhibitor treatment, albuminuria
was 2.94 1.92 mg/24 h; BP was 137/76 mmHg; K+ was 4.8 0.5 mmol/l, Cr
was 1.76 0.67 mg/dL, and CrC was 62 31.9 mL/min. After 6 months, dual
blockade of the RAS albuminuria was 2.18 2.29 mg/24 h (P < 0.01 vs. baseline) and BP was 133/75 mmHg (not significant). At 36 months, albuminuria
was 2.21 2.20 mg/24 h (P < 0.05 vs. baseline); BP was 133/73 mmHg (not
significant). CrC was not changed along the follow up. A small increment of Cr
was detected at 24 months (2.11 1.06 mg/mL, P < 0.05). The antiproteinuric
effect of dual reninangiotensin system blockade combining candesartan and
ACE inhibitors remain after 36 months without losing its initial effect. Blood
pressure changes seem not to explain this long-term antiproteinuric effect.

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

c 2009 Blackwell Publishing Ltd

Cardiovascular Therapeutics 27 (2009) 101107 

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

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Long-Term Dual RAS blockade

published, but they are related to microalbuminoric,

nonproteinuric, patients. [24] However, even dual RAS
blockade, might be incomplete and lost effectiveness after some time due to several mechanisms as non-RAS
stimulators, [25] aldosterone breakthrough, [26] or a vicious cycle within the RAS in which aldosterone might
perpetuate both the expression of ACE [27] and that of
AII type 1 receptor. [28] To evaluate the persistence of
the antiproteinuric effect of dual RAS blockade, we have
conducted a 3-year trial on proteinuric patients (either
diabetics or nondiabetics) treated with an ARB added on
pretreatment with full doses of ACE inhibitors.

Design and Methods

Twenty-eight patients were recruited in our unit for
treatment with dual RAS blockade due to proteinuria
higher than 1 g/24 h. Of them, 25 patients complete 36
months of follow up after starting treatment. Dual blockade was used when the patient have proteinuria higher
than 1 g/24 h and diastolic blood pressure <80 mmHg.
Twenty patients have chronic renal failure (CRF) at
baseline (plasmatic creatinine > 1.5 mg/dL and/or creatinine clearance < 60 mL/min for more than 6 months
previously to be enrolled). Mean age was 58 12.4 years;
they were 13 men and 7 women. Mean plasmatic creatinine was 2.40 0.45 mg/dL and average creatinine
clearance was 48.7 19 mL/min. K/DOQI stages of renal disease were: Stage I, 5; Stage II, 8; Stage III, 11; and
Stage IV, 4 patients.
Patients were treated with an additional 4 to 32 mg
of candesartan in addition to concomitant ACE inhibitors
treatment. Candesartan dosage was cautiously titrated
up to maximal tolerated dose. For safety reasons, candesartan dosage was decreased or even interrupted if the
systolic blood pressure fell below 100 mmHg or kaliemia
increased above 6.5 mmol/L. If a patients systolic blood
pressure was above 160 mmHg or diastolic blood pressure above 90 mmHg, additional antihypertensive drugs
could be added to the patients treatment regimen. Mean
final dose of candesartan was 17.1 mg/day (minimum
8, maximum 32 mg/day). Only one patient needs to
add hydrochlorotiazide (12.5 mg once daily to treatment.
ACE inhibitors and candesartan dosage are shown in
Table 1.
The follow-up period was 36 months, with at least 10
visits at the clinic (after 2 week and after 1, 3, 6, 9, 12,
18, 24, 30, and 36 months). At each visit, seated blood
pressure was measured at the trough level after 15 min of
rest with sphygmomanometry using an appropriate cuff.
Blood pressure was measured three times, after which the
mean was calculated. Data of 6, 12, 24, and 36 months

102

N.R. Robles et al.

Table 1 General characteristics of the sample

Mean age

57.0 14.8 years

Gender
Causes of proteinuria
Diabetic nephropathy
Idiopathic chronic
glomerulonephritis
Interstitial nephritis
Hypertensive nephropathy
Hyperltration
glomerulopathy on single
functioning kidney
Alport disease

Male 19 (67.9%), female 9 (32.1%)

10
6
4
3
3

visit have been recorded including: plasmatic creatinine,

kaliemia, total proteins, albumin, as well as proteinuria
and creatinine clearance measured through 24 h urine
collection method.
Results are expressed as mean 1 standard deviation.
KolmogorofLilliefors Test showed that proteinuria did
not follow a normal distribution so these values were
compared using Wilcoxon test for paired data. Other continuous values have been compared through paired Student t test but the comparison between CRF patients and
the rest of the sample where ANOVA test was performed.
The chi square test was used for discrete data. All statistical tests were two-sided. P values lower than 0.05
were considered as significant. Analysis was developed
with the statistical package SPSS 13.0 (SPSS, Chicago, IL,
USA).
This work has not received any financial or material support neither from pharmaceutical enterprises nor
from public health or scientific organizations.

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

c 2009 Blackwell Publishing Ltd

Cardiovascular Therapeutics 27 (2009) 101107 

Long-Term Dual RAS blockade

N.R. Robles et al.

Table 2 Last visit drugs dosage

Patient

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.

Figure 1 Proteinuria was signicantly reduced after starting combined

treatment (ARB plus ACE inhibitors) and this effect remains after 36 months
follow up.

significantly increased in each visit after the combined

treatment was started (see also Table 3), but changes of
creatinine clearance were only significant after completing 36 months of follow up (baseline, 60.7 31.8 mg/dL;

c 2009 Blackwell Publishing Ltd

Cardiovascular Therapeutics 27 (2009) 101107 

36th month, 54.7 38.3, P = 0.006, Student t test) (other

values in Table 3).
At baseline plasmatic creatinine was higher in CRF
group (2.10 0.45 vs. 0.93 0.23 mg/dL, P < 0.001,
Student t test) and creatinine clearance was lower
(48.7 19 vs. 95.1 34.5 mL/min, P = 0.006, Student
t test). There was a small increase in creatinine along the
follow up when compared with normal renal function
group (P < 0.001, analysis of variance [ANOVA]). Conversely, creatinine clearance remains unchanged in normal renal function group and decrease in CRF patients
(P < 0.001). Values are showed in Table 5.

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

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N.R. Robles et al.

Table 3 Proteinuria and blood pressure changes

Month

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.

Figure 2 Changes on SBP were only signicant at 6 months visit (see

signicance in text). There were not signicant changes in DBP.

[34]; so that, ACE escape might be more pronounced

in patients with renal disease. ACE inhibitors also inhibit the ACE2 enzyme, and thus reduce production
of Angiotensin (17), an endogenous antagonist of Angiotensin II action that is produced by ACE2. [35] On

the other hand, ARB block the action of angiotensin II

at the receptor level, regardless of its origin. However,
ARB cause rebound increases in plasma renin and Angiotensin II concentrations by interrupting negative feedback. As the renal RAS is compartmentalized from the
systemic RAS, [36] which means that doses of ACEI inhibitors or ARB necessary to inhibit the intrarenal RAS
may be greater than those required for maximal effects on
blood pressure. Therefore, tissue concentrations of ARB
may be insufficient to overcome the rebound increase
in angiotensin II, even with doses that produce maximal reductions in systemic blood pressure. [37] Interestingly, animal studies demonstrated that a combination of
an ACEI and an ARB reduced renal angiotensin II concentrations to a greater extent than did greater doses of
either drug alone. [38] This suggests that combination
treatment may result in less ACE escape, less generation
of Angiotensin 4, which has the same of angiotensin II
in the kidney, [39] and less stimulation of AT2 and AT4receptors. Nevertheless, even dual blockade of RAS might

Table 4 Serum parameters

Month

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

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Cardiovascular Therapeutics 27 (2009) 101107 

Long-Term Dual RAS blockade

N.R. Robles et al.

be incomplete and lost its antiproteinuric properties after

some time of treatment as related previously. [2427] In
this way, most cumulated evidence on dual RAS blockade
is based on very short trials, usually 6 months or less of
follow up time. [49,1123] Only one trial gets 2.9 years
of follow up; in this study the ARB and the combination
groups, once maximum antiproteinuric effects had been
obtained, proteinuria remained constant during the period of the trial. [10] In the ACE inhibitor group, proteinuria gradually decreased over time. Our results confirm
the long-term efficacy of dual RAS blockade to decrease
proteinuria and hold this reduction without neither rebound nor further decrease as long as 3 years of follow
up.
On the clinical ground, there is a lonely trial that shows
that the combination of an ACE inhibitor with an ARB affords greater renoprotection (in terms of lengthening renal failure progression) than each drug used alone. The
COOPERATE Study [10] showed that 11% of patients
who receiving combination treatment reached the combined primary end point of time to doubling of serum
creatinine concentration or end-stage renal disease compared with 23% of patients who were receiving an ACE
inhibitor or an ARB alone. In the other hand, a possible
untoward effect of dual RAS blockade is a slight (seldom
severe) increase of plasmatic creatinine due to a fall in
renal function. [40] We do not detect any change in plasmatic creatinine among patients with normal renal function along the study period. In the CRF group occurs a
small but steadily increase of plasmatic creatinine, which
seems to be related to the progressive curse of renal disease more than to the acute or chronic effect of dual RAS
blockade.
A possible explanation of the effect of dual RAS blockade in renal disease is a merely reduction of systemic
blood pressure. It has been reported that when the ACE
inhibitor dose is titrated to obtain the same blood pressure
decrease as the combination, no difference in the antiproteinuric effect is observed. [22] Some studies have shown
a greater antiproteinuric action of the combination, associated, however, with a greater blood pressure reduction. [8,19] Conversely, most of the other studies suggest
that dual RAS blockade may exert a significantly greater
antiproteinuric action than single blockade without any
increment of the antihypertensive effect. [47,923,38]
Some (but not all) available studies have been included
in a recent meta-analysis which has found the greater
antiproteinuric action of the combination was associated
with a greater blood pressure lowering. [41] In our study
there was only a significant change in DBP at 12 months
and so that, the observed change seems not be explained
by a decline in systemic BP. In this regard, these results
agreed with most of the cumulated experience.

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Cardiovascular Therapeutics 27 (2009) 101107 

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.

References
1. Lakkis J, Lu WX, Weir MR. RAAS escape: A real clinical
entity that may be important in the progression of
cardiovascular and renal disease. Curr Hypertens Rep
2003;5:408417.
2. Taal MW, Brenner BM. Renoprotective benefits of RAS
inhibition: From ACEI to angiotensin II antagonists.
Kidney Int 2000;57:18031817.
3. Wolf G, Butzmann U, Wenzel UO. The reninangiotensin
system and progression of renal disease: From
hemodynamics to cell biology. Nephron Physiol
2003;93:313.
4. Russo D, Minutolo R, Pisani A, Esposito R, Signorello G,
Andreucci M, Belleta MM. Coadministration of losartan
and enalapril exerts additive antiproteinuric effect in IgA
nefropathy. Am J Kidney Dis 2001;38:1825.
5. Ruilope LM, Aldigier JC, Ponticelli C, Oddou-Stock P,
Botteri F, Mann JF. Safety of the combination of valsartan

105

Long-Term Dual RAS blockade

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

106

and benazepril in patients with chronic renal disease.

European Group for the Investigation of Valsartan in
Chronic Renal Disease. J Hypertens 2000;18:8995.
J, Barrio V, Goicoechea MA, et al. Effects of dual
Luno
blockade of the reninangiotensin system in primary
proteinuric nephropathies. Kidney Int 2002;62(Suppl.
82):S47S52.
Jacobsen P, Andersen S, Rossing K, Hansen BV, Parving
HH. Dual blockade of the reninangiotensin system in
type 1 patients with diabetic nephropathy. Nephrol Dial
Transplant 2002;17:10191024.
Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R,
Watts RW, Cooper ME for the CALM study group.
Randomised controlled trial of dual blockade of
reninangiotensin system in patients with hypertension,
microalbuminuria, and non-insulin dependent diabetes:
The candesartan and lisinopril microalbuminuria (CALM)
study. BMJ 2000;321:14401444.
Kunz R, Friedrich C, Wolbers M, Mann JFE.
Meta-analysis: Effect of monotherapy and combination
therapy with inhibitors of the reninangiotensin system
on proteinuria in renal disease. Ann Intern Med
2008;148:3048.
Nakao N, Yoshimura A, Morita M, Kayano T, Ideura T.
Combination treatment of angiotensin-II receptor blocker
and angiotensin-converting-enzyme inhibitor in
non-diabetic renal disease (COOPERATE): A randomised
controlled trial. Lancet 2003;361:117124.
Doulton TW, He FJ, MacGregor GA. Systematic review of
combined angiotensin-converting enzyme inhibition and
angiotensin receptor blockade in hypertension.
Hypertension 2005;45:880886.
Chandar J, Abitbol C, Montane B, Zilleruelo G.
Angiotensin blockade as sole treatment for proteinuric
kidney disease in children. Nephrol Dial Transplant
2007;22:13321337.
Krimholtz MJ, Karalliedde J, Thomas S, Bilous R, Viberti
G. Targeting albumin excretion rate in the treatment of
the hypertensive diabetic patient with renal disease. J Am
Soc Nephrol 2005;16(Suppl 1):S42547.
Fujisawa T, Ikegami H, Ono M, et al. Combination of half
doses of angiotensin type 1 receptor antagonist and
angiotensin-converting enzyme inhibitor in diabetic
nephropathy. Am J Hypertens 2005;18:1317.
Matos JP, de Lourdes Rodrigues M, Ismerim VL,
Boasquevisque EM, Genelhu V, Francischetti EA. Effects
of dual blockade of the renin angiotensin system in
hypertensive type 2 diabetic patients with nephropathy.
Clin Nephrol 2005;64:180189.
Sengul AM, Altuntas Y, Kurklu A, Aydin L. Beneficial
effect of lisinopril plus telmisartan in patients with type 2
diabetes, microalbuminuria and hypertension. Diabetes Res
Clin Pract 2006;71:210219.
Schjoedt KJ, Jacobsen P, Rossing K, Boomsma F, Parving
HH. Dual blockade of the reninangiotensin-aldosterone

N.R. Robles et al.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

system in diabetic nephropathy: The role of aldosterone.

Horm Metab Res 2005;37(Suppl 1):48.
Rutkowski P, Tylicki L, Renke M, Korejwo G, Zdrojewski
Z, Rutkowski B. Low-dose dual blockade of the
reninangiotensin system in patients with primary
glomerulonephritis. Am J Kidney Dis 2004;43:
260268.
Kincaid-Smith P, Fairley K, Packham D. Randomized
controlled crossover study of the effect on proteinuria and
blood pressure of adding an angiotensin II receptor
antagonist to an angiotensin converting enzyme inhibitor
in normotensive patients with chronic renal disease and
proteinuria. Nephrol Dial Transplant 2002;17:
597601.
Kuriyama S, Tomonari H, Tokudome G, et al.
Antiproteinuric effects of combined antihypertensive
therapies in patients with overt type 2 diabetic
nephropathy. Hypertens Res 2002;25:849855.
Kim MJ, Song JH, Suh JH, Lee SW, Kim GA. Additive
antiproteinuric effect of combination therapy of ACE
inhibitor and angiotensin ii receptor antagonist:
Differential short-term response between IgA
nephropathy and diabetic nephropaty. Yonsei Med J
2003;44:463472.
Andersen NH, Poulsen PL, Knudsen ST, et al. Long-term
dual blockade with candesartan and lisinopril in
hypertensive patients with diabetes: The CALM II study.
Diabetes Care 2005;28:273277.
Bakris GL, Ruilope L, Locatelli F, et al. Treatment of
microalbuminuria in hypertensive subjects with elevated
cardiovascular risk: Results of the IMPROVE trial. Kidney
Int 2007;72:879885.
Mann JF, Schmieder RE, McQueen M, et al. Renal
outcomes with telmisartan, ramipril, or both, in people at
high vascular risk (the ONTARGET study): A multicentre,
randomised, double-blind, controlled trial. Lancet
2008;372:547553.
Okubo S, Niimura F, Nishimura H, Takemoto F, Fogo A,
Matsusaka T, Ichikawa I: Angiotensin-independent
mechanism for aldosterone synthesis during chronic
extracellular fluid volume depletion. J Clin Invest
1997;99:855860.
Sato A, Saruta T: Aldosterone escape during
angiotensinconverting enzyme inhibitor therapy in
essential hypertensive patients with left ventricular
hypertrophy. J Int Med Res 2001;29:1321.
Harada E, Yoshimura M, Yasue H, et al: Aldosterone
induces angiotensin-converting-enzyme gene expression
in cultured neonatal rat cardiocytes. Circulation
2001;104:137139.
Robert V, Heymes C, Silvestre JS, Sabri A, Swynghedauw
B, Delcayre C. Angiotensin AT1 receptor subtype as a
cardiac target of aldosterone: Role in
aldosterone-salt-induced fibrosis. Hypertension
1999;33:981986.

c 2009 Blackwell Publishing Ltd

Cardiovascular Therapeutics 27 (2009) 101107 

Long-Term Dual RAS blockade

N.R. Robles et al.

29. Wilmer WA, Rovin BH, Hebert CJ, Rao SV, Kumor K,
Hebert LA. Management of glomerular proteinuria: A
commentary. J Am Soc Nephrol 2003;14:32173232.
30. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of
progression and regression of renal lesions of chronic
nephropathies and diabetes. J Clin Invest
2006;116:288296.
31. Zoccali C, Valvo E, Russo D, Panichi V, Zuccala A.
Anti-proteinuric effect of losartan in patients with chronic
renal diseases. Nephrol Dial Transplant 1997;12:
234235.
32. Sicca DA. Combination ACE inhibitor and angiotensin
receptor blocker therapyfuture considerations. J Clin
Hypertens 2007;9:7886.
33. Richard V, Hurel-Merle S, Scalbert E, Ferry G, Lallemand
F, Bessou JP, Thuillez C. Functional evidence for a role of
vascular chymase in the production of angiotensin II in
isolated human arteries. Circulation 2001;104:750752.
34. Huang XR, Chen WY, Truong LD, Lan HY. Chymase is
upregulated in diabetic nephropathy: Implications for an
alternative pathway of angiotensin II-mediated diabetic
renal and vascular disease. J Am Soc Nephrol
2003;14:17381747.
35. Tikellis C, Johnston CI, Forbes JM, Burns WC, Burrell
LM, Risvanis J, Cooper ME. Characterization of renal

c 2009 Blackwell Publishing Ltd

Cardiovascular Therapeutics 27 (2009) 101107 

36.

37.

38.

39.

40.

41.

angiotensin-converting enzyme 2 in diabetic

nephropathy. Hypertension 2003;41:392397.
Nishiyama A, Seth DM, Navar LG. Renal interstitial fluid
concentrations of angiotensins I and II in anesthetized
rats. Hypertension 2002;39:129134.
Wolf G, Ritz E. Combination therapy with ACE inhibitors
and angiotensin II receptor blockers to halt progression of
chronic renal disease: Pathophysiology and indications.
Kidney Int 2005;67:799812
Komine N, Khang S, Wead LM, Blantz RC, Gabbai FB.
Effect of combining an ACE inhibitor and an angiotensin
II receptor blocker on plasma and kidney tissue
angiotensin II levels. Am J Kidney Dis 2002;39:159164.
Roks AJM, Henning RH. Angiotensin peptides: Ready to
re(de)fine the angiotensin system?. Journal of Hypertension
2003;21:12691271.
Robles NR, Cancho B, Barroso S, Martin MV, Sanchez
Casado E. Untoward effects of dual rennin-angiotensis
system blockade: Influence of previous chonic renal
failure. Intl J Clin Pract 2006;60:10351039.
MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J,
Clark HD. Combination therapy with an angiotensin
receptor blocker and an ACE inhibitor in proteinuric
renal disease: A systematic review of the efficacy and
safety data. Am J Kidney Dis 2006;48:820.

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