Journal of Renin-Angiotensin-Aldosterone

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Review: Renal protection by inhibition of the renin-angiotensin-aldosterone system

Tomas Berl
Journal of Renin-Angiotensin-Aldosterone System 2009 10: 1
DOI: 10.1177/1470320309102747
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Review

Renal protection by inhibition of the renin-angiotensinaldosterone system

Tomas Berl

Correspondence to:
Tomas Berl, MD
Division of Renal
Diseases and
Hypertension,
University of Colorado
at Denver Health
Sciences Center,
4200 East Ninth
Avenue, Box C281,
BRB 423, Denver, CO
80262, USA.
Tel: +1 303 315 7204
Fax: +1 303 315 0189
Email: Tomas.Berl@
uchsc.edu

Abstract
Renin-angiotensin-aldosterone system (RAAS)
inhibition exerts a renoprotective effect
independent of blood pressure reduction. Many
studies using an end-point of proteinuria compared
the effects of angiotensin-converting enzyme
inhibitor (ACE-I) or angiotensin receptor blocker
(ARB) monotherapy with combination ACE-I/ARB
therapy. Despite methodological limitations, most
studies suggest that combination therapy provides a
greater antiproteinuric effect than monotherapy,
perhaps because of more prolonged and complete
RAAS inhibition. COOPERATE and ONTARGET
used more robust end-points to study
renoprotective effects. In COOPERATE,
combination therapy resulted in significantly longer
times to doubling serum creatinine or developing
end-stage renal disease than trandolapril or losartan
monotherapy. However, a secondary ONTARGET
finding was that combination therapy significantly
increased the risk for renal dysfunction compared
with ramipril or telmisartan alone. Eventually, the
VA NEPHRON-D trial should provide definitive data
relating to patients with diabetic nephropathy.
Results of AVOID suggest the renoprotective
benefits of combination therapy extend to the
direct renin inhibitors (DRI). In AVOID,
combination therapy with aliskiren, a DRI, and
losartan resulted in 20% greater protein excretion
decrement than losartan monotherapy. Future trials
should examine higher RAAS inhibitor doses,
facilitate differentiation of renoprotective and
antihypertensive effects of RAAS blockade, and use
end-points that robustly demonstrate
renoprotective effects.

Journal of
the ReninAngiotensinAldosterone
System
(Including other
Peptidergic systems)

Introduction
In the past 20 years, inhibitors of the reninangiotensin-aldosterone system (RAAS) have
become a cornerstone for the treatment of hypertension. Similarly, RAAS inhibitors have been

Key words:
angiotensinconverting
enzyme
inhibitor,
angiotensin
receptor blocker,
combination
therapy, direct
renin inhibitor,
monotherapy,
proteinuria

Division of Renal
Diseases and
Hypertension, University
of Colorado at Denver
Health Sciences Center,
Denver, Colorado, USA.

used increasingly in patients with underlying

renal disease as mounting evidence has pointed
to the agents having an antiproteinuric effect that
is independent of blood pressure lowering.1 This
effect is considered important in light of two key
observations. Several large interventional studies
have uniformly found that proteinuria is a major
risk factor for the progression of renal disease.2-5
Furthermore, the reduction of proteinuria in
patients with underlying diabetic nephropathy
has been associated with a decreased risk for a
renal end-point (e.g. doubling of serum creatinine, reaching end-stage renal disease).3,4 A similar observation was seen in patients with
nondiabetic kidney disease with lower levels of
baseline proteinuria,5 thereby demonstrating the
importance of lowering protein excretion in a
variety of renal disorders and across a broad
spectrum of protein excretions.
In view of these observations, it is not surprising
that clinical studies have evaluated the effects of
higher doses of angiotensin-converting enzyme
inhibitors (ACE-I)6,7 and angiotensin receptor blockers (ARB)6,8 at doses exceeding those approved by
the Food and Drug Administration for lowering
blood pressure. Additionally, because RAAS intervention can be targeted at various points (figure
1), it has been postulated that combining more
than one of these intervention points could lead to
greater inhibition of the RAAS and a more robust
decrement in protein excretion. Thus, there are
four potential combinations of existing therapeutic
agents. Furthermore, given that antagonists of
aldosterone a downstream effector of angiotensin
II (Ang II) have been shown to decrease protein
excretion in patients with renal diseases,9 the
option of also using aldosterone inhibitors doubles
the potential combinations to eight. In this review, a
brief summary of the data is presented supporting
the use of combination therapy with ACE-Is and
ARBs compared with monotherapy using either

March 2009
Volume 10
Number 1
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10.1177/1470320309102747

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Review

Figure 1
RAAS and points at which pharmacologic intervention can inhibit it. ACE = angiotensin-converting enzyme; ARB = angiotensin
receptor blocker; AT1 = angiotensin II type 1; DRI = direct renin inhibitor.

class of agents. Also presented are some results of

emerging studies with a recently approved direct
renin inhibitor (DRI), aliskiren.
Comparison of the effects of
combination ACE-I plus ARB therapy
with ACE-I or ARB monotherapy on
proteinuria
A large number of clinical studies have compared
the effects of dual RAAS blockade and single
blockade with an ACE-I or an ARB on protein
excretion as a surrogate for renal protection. The
reader is referred to tables 4 and 5 in the metaanalysis conducted on these studies by Kunz et al.10
Details of some of these studies, which are representative of the group as a whole, are presented
in table 1.11-17

Journal of
the ReninAngiotensinAldosterone
System
(Including other
Peptidergic systems)
March 2009
Volume 10
Number 1

Mogensen et al.11 were the first investigators to

conduct a randomised, parallel-group, doubleblind study comparing lisinopril 20 mg, candesartan
16 mg, and combination lisinopril plus candesartan
in 199 patients with type 2 diabetes. Combination
therapy with lisinopril plus candesartan provided
a significant decrease in protein excretion compared
with ARB monotherapy (p=0.04); however, the
difference was not significant when compared
with ACE-I monotherapy. In a small follow-up
study (n=20), Jacobsen et al.12 compared the antiproteinuric effects of benazepril 20 mg, valsartan
80 mg, and combination therapy with benazepril
plus valsartan in a randomised, double-blind,
placebo-controlled, crossover trial in patients

with type 1 diabetes. In contrast to the Mogensen

et al. findings,11 a significant decrease in protein
excretion was reported in the patients treated
with benazepril 20 mg plus valsartan 80 mg compared with patients treated with monotherapy of
either agent (p<0.05).12
In a study with similar design, Jacobsen et al.13
evaluated the effect of enalapril 40 mg, irbesartan
300 mg, and combination therapy with enalapril
plus irbesartan in 24 patients with type 1 diabetes. Repeatedly, the combination of the ACE-I and
ARB provided a significantly greater antiproteinuric effect than therapy with the ACE-I alone
(p<0.001).
Although these often-cited studies support the
clinical use of dual RAAS inhibition with an ACE-I
and an ARB, two study limitations may impact this
interpretation in clinical practice. The first limitation relates to the difference in achieved blood
pressure measurements among the treatment
groups. Specifically, in the study by Mogensen et
al.,11 the authors clearly state that in the group of
patients who received the combination treatment
after 12 weeks, there was a measurable further
reduction in systolic and diastolic blood pressure.
Similarly, the two studies by Jacobsen et al.12,13
report 7 mmHg to 9 mmHg lower systolic and
diastolic ambulatory blood pressure in the group
receiving ACE-I/ARB combination therapy. It is
therefore difficult, if not impossible, to ascertain
whether the changes observed in protein excretion

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Table 1
Combination of ACE-I plus ARB versus ACE-I or ARB.

Combination
better than

monotherapy Blood pressure

No. of patients
lower in
Reference
End-point
Condition
Drugs
ACE-I ARB combination

Mogensen et al.11 UACR

n=199
Lisinopril 20 mg or candesartan

Type 2 diabetes 16 mg vs. lisinopril 20 mg +
candesartan 16 mg

No

Yes

Yes

Jacobsen et al.12 Urinary

n=20
Benazepril 20 mg or valsartan
albumin
Type 1 diabetes 80 mg vs. benazepril
20 mg + valsartan 80 mg

Yes

Yes

Yes

Jacobsen et al.13 Urinary

albumin

n=24
Type 1 diabetes

Yes

Yes

Luno et al.14
UACR

n=45
Lisinopril to 40 mg or candesartan Yes
Proteinuric to 32 mg vs. lisinopril
nephropathy 20 mg + candesartan 16 mg

Yes

No

Campbell et al.15 UACR

n=24
Benazepril 20 mg or valsartan
Nondiabetic 160 mg vs. benazepril
proteinuria 10 mg + valsartan 80 mg

Yes

Yes

No

Nakao et al.16
Doubling
serum
creatinine
ESRD

n=263
Trandolopril 3 mg or losartan
Nondiabetic 100 mg vs. trandolopril
proteinuria 3 mg + losartan 100 mg

Yes

Yes

No

The ONTARGET Doubling serum n=25,620

Telmisartan 80 mg or ramipril
Investigators17 creatinine 10 mg vs. telmisartan
ESRD Death 80 mg + ramipril 10 mg

No

No

Yes

Enalapril 40 mg vs. enalapril

40 mg + irbesartan 300 mg

Key: ESRD = end-stage renal disease; UACR = urinary albumin/creatinine ratio.

were a consequence of more complete RAAS

inhibition or decreased blood pressure. The second study limitation was the dosing used, which
may in fact be partially responsible for the
observed changes in blood pressure. Therefore,
all three of these studies and two other studies18,19
administered the same doses of ACE-I and ARB
as monotherapy and as combination therapy,
which might have resulted in more complete
inhibition of RAAS with combination therapy
than was achieved with either drug administered
as monotherapy. This factor is particularly important because some studies have reported that the
use of megadoses of monotherapy with ACE-Is or
ARBs are associated with positive changes in protein excretion comparable to those reported
using combination therapy with an ACE-I plus an
ARB.6-8
Journal of
the ReninAngiotensinAldosterone
System
(Including other
Peptidergic systems)
March 2009
Volume 10
Number 1

Several recent studies have avoided these design

limitations. In a study of 45 patients with primary
proteinuric nephropathies (>2 g protein/d), Luno
et al.14 described a significant decrease (p=0.023)
in protein excretion with combination therapy of
lisinopril (up to 20 mg) plus candesartan (up to 16
mg) versus monotherapy with either drug given at

up to twice the original dose (lisinopril [up to 40

mg]; candesartan [up to 32 mg]; table 1). This
dosing approach is more appropriate than the
study design used in the earlier reports because
it may provide equivalent RAAS inhibition in all
treatment groups.11-13,18,19 The study by Luno
et al.,14 though limited in the number of patients
enrolled, had merit in that it achieved equivalent
blood pressure levels in all three treatment
groups. Combination therapy with an ACE-I and
an ARB resulted in a greater decrease in proteinuria than did monotherapy.
A similar observation was reported by Campbell
et al. 15 in a prospective, randomised, crossover
study of 24 nondiabetic patients with proteinuria. Similar to the study design used by Luno
et al.,14 Campbell et al.15 administered twice the
dose of an ACE-I (benazepril 20 mg) or an ARB
(valsartan 160 mg) as monotherapy compared
with the doses used for combination therapy
(benazepril 10 mg plus valsartan 80 mg).
This study design resulted in identical decreases
in blood pressure reported as mean arterial
pressure: 95 mmHg (benazepril 20 mg), 95
mmHg (valsartan 160 mg), and 94 mmHg

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Figure 2
Percentage change from baseline for 24-hour urinary protein
excretion rate, mean arterial pressure, and creatinine clearance.
p<0.025 with Bonferroni adjustment. Data are meanSEM;
n=24. Dosages: valsartan 160 mg; benazepril 20 mg; benazepril
+ valsartan 10 mg + 80 mg.15 Reprinted with permission from
Campbell R, Sangalli F, Perticucci E et al. Effects of combined
ACE inhibitor and angiotensin II antagonist treatment in human
chronic nephropathies. Kidney Int 2003;63:1094-103.

(benazepril 10 mg plus valsartan 80 mg).

Although monotherapy with benazepril or valsartan lowered the albumin/creatinine ratio by
45.9% or 41.5%, respectively, combination therapy lowered the albumin/creatinine ratio by
56.0%, which was statistically greater than was
achieved with either monotherapy (figure 2).15
These blood pressure-lowering independent
effects of combination therapy at comparable
doses were subsequently reported by others.20

Journal of
the ReninAngiotensinAldosterone
System
(Including other
Peptidergic systems)
March 2009
Volume 10
Number 1

It must be noted that not all clinical studies

uniformly report a positive response from combination treatment with an ACE-I plus an ARB,
even when proper dose adjustments have been
made. For example, Esnault et al.21 found no
greater decrement in protein excretion in 18
proteinuric patients given ramipril 5 mg plus
valsartan 80 mg compared with ramipril 10 mg
or valsartan 160 mg. However, this study suggests,
as has been previously proposed by others,22,23
that the concomitant sodium balance may be
another important determinant of the response
to inhibitors of RAAS. Thus, patients who received
ACE-I/ARB combination therapy displayed
marked reductions in protein excretion when
they were also given the diuretic furosemide.
However, in the study by Esnault et al.,21 furosemide was not given to the monotherapy
groups and was associated with significant decrements in systolic blood pressure.
Most studies of RAAS blockers comparing the antiproteinuric effect of monotherapy with combination therapy lack sufficient power to establish a
difference between the regimens. Therefore, a
meta-analysis of existing studies was undertaken
by Doulton et al.24 The meta-analysis included

analysis of eight independent clinical studies; it

found that combination ACE-I/ARB therapy
decreased protein excretion by 30% compared with
ACE-I monotherapy and by 39% with ARB monotherapy. A more recent and exhaustive meta-analysis compared the antiproteinuric effect in the early
phase (14 months) and the later phase (512
months) of treatment.10 In the early phase of treatment, 14 studies were analysed to compare the
antiproteinuric effects of combination therapy with
an ACE-I plus ARB with those of ARB monotherapy. The ratio of means (95% confidence interval [CI]) favoured combination treatment (0.76
[0.680.85]). A similar result was observed in 21
studies when the comparator was ACE-I monotherapy (0.78 [0.720.84]). In the later phase of
treatment, a smaller group of studies was available
for analysis. Nonetheless, combination therapy was
found to be superior to ARB monotherapy in seven
studies (0.75 [0.610.92]). In the same studies, the
ratio of means was 0.82 (0.671.01) when the comparator was ACE-I monotherapy. Evaluated together,
these data suggest that combining an ACE-I and an
ARB may provide a superior antiproteinuric effect
than monotherapy with either agent. However, the
superiority may be limited to conventional doses of
ACE-Is and ARBs because higher than conventional
doses of these agents also decrease protein
excretion.6-8,25 For example, in one of these studies,
Hollenberg et al.8 found that 320 mg and 640 mg of
valsartan provide further antiproteinuric effect
when compared to conventional dose of 160 mg.
Thus, in the appropriate clinical setting, this
approach may yield results that are comparable to
combination therapy. No studies have been published comparing the two approaches.
The underlying, unifying mechanism for inhibition of the RAAS may be the degree of inhibition
of the system and of the generation of Ang II.
This is strongly suggested by the observations of
a study by Forclaz et al.,26 who investigated the
antihypertensive response of monotherapy and
combination therapy of two ARBs (losartan and
telmisartan) on angiotensin I (Ang I) infusion
(figure 3) in normotensive persons.26 As expected,
blockade of Ang II generation was not observed
with standard doses of either ARB, but inhibition
of blood pressure response to Ang I was seen
when the dose of losartan (a short-acting ARB)
was increased to 100 mg twice a day or when a
standard dose of telmisartan (a long-acting ARB)
was combined with the ACE-I. As Linas27 suggests, these results support the view that the
critical determinant of blood pressure response is
longer (a full 24 hours) and more complete inhibition of the RAAS rather than physiologic interaction between an ACE-I and an ARB, as supported
by the data depicted in figure 3.

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Figure 3
Summary of blockade of blood pressure (BP) response to exogenous angiotensin I at trough in study groups (n=510 according
to study protocols). Data are meanSD; *p<0.01; bid = twice a day; qd = every day.26 Reprinted with permission from Forclaz A,
Maillard M, Nussberger J, Brunner HR, Burnier M. Angiotensin II receptor blockade: is there truly a benefit of adding an ACE
inhibitor? Hypertension 2003;41:31-6.

Journal of
the ReninAngiotensinAldosterone
System
(Including other
Peptidergic systems)
March 2009
Volume 10
Number 1

Renoprotection with combination ACE-I

plus ARB therapy
All the aforementioned studies used change in
protein excretion as a surrogate for renal protection. A more robust end-point of renal protection
is the ability of an intervention to alter the time to
renal failure in patients with progressive renal disease. No review of this subject would be complete
without a brief discussion of the COOPERATE trial,
which compared ACE-I/ARB combination therapy
with monotherapy and used a combined endpoint of time to doubling serum creatinine or
development of end-stage renal disease (table 1).16
In this study, 263 patients with moderately
advanced renal insufficiency (glomerular flow rate,
approximately 35 ml/min) were followed up for a
median of 2.9 years (range, 3 months3.3 years).
The COOPERATE trial was terminated early
because of the beneficial effect observed with
combination therapy. Specifically, the hazard ratio
of combination therapy compared with losartan
monotherapy was 0.40 (95% CI, 0.170.69;
p=0.016); compared with trandolapril monotherapy
it was 0.38 (95% CI, 0.180.63; p=0.018). This
effect occurred across the spectrum of baseline
protein excretion and was independent of lowered
blood pressure because it was similarly decreased
in all three treatment groups. However, analysis of
the ambulatory blood pressures in this study has
raised questions about whether the effect was
truly blood pressure independent.28 Furthermore,
serious concerns have been raised about the accuracy of the data and their analysis,29 that if verified
should lead to a negation of the trial.

The effects of combination therapy on renal function were markedly different in the ONTARGET
trial, whose final results have recently been published.17 ONTARGET included 25,620 patients
85% with cardiovascular disease, 69% with
hypertension, and 38% with diabetes who were
randomly assigned to receive ramipril 10 mg,
telmisartan 80 mg, or combination therapy. This
was not a trial of patients with underlying renal
disease because renal function at baseline was
normal and only 13% of the patients had microalbuminuria. During the study, mean blood pressure was slightly lower in groups treated with
telmisartan (a 0.9/0.6 mmHg greater reduction)
and combination therapy (a 2.4/1.4 mmHg greater
reduction) than in the group treated with ramipril
(table 1). However, these did not result in a significant benefit in terms of the primary composite
outcome (death from cardiovascular cause,
myocardial infarction, or stroke or hospitalisation
for heart failure). At a median follow-up of 56
months, the primary outcome had occurred in
16.5% of the ramipril group and 16.7% of the telmisartan group, indicating that telmisartan was
noninferior to, but not superior to, ramipril (relative risk, 1.01; 95% CI, 0.941.09). Similarly, the
primary outcome occurred in 16.3% of the combination therapy group (relative risk vs. ramipril,
0.99; 95% CI, 0.921.07).17
Nephropathy was a secondary outcome of
ONTARGET and the renal outcomes have been
recently published.30 The primary renal outcome
was the composite of dialysis, doubling of serum

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Figure 4
Kaplan-Meier curves for primary renal outcome (dialysis, doubling of serum creatinine, and death).30 Reprinted with permission
from 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;372:547-53.

creatinine and death. While the telmisartan and

ramipril arms did not differ from each other, the
number of events was increased in the combination
HR 1.09 [1.101.18], p=0.037 (figure 4). The secondary outcomes of dialysis and doubling of serum
creatinine were also higher in the combination
group. It must be pointed out that the great majority of the patients in this trial had normal renal
function and were free of proteinuria. In fact, a
subgroup analysis suggests that the worse outcome
with the combination therapy occurred in patients
who were not diabetic, not hypertensive, had neither micro nor macroalbuminuria, and had no over
diabetic nephropathy. A study primarily aimed at
patients at risk for progressive renal disease is
still needed.

Journal of
the ReninAngiotensinAldosterone
System
(Including other
Peptidergic systems)
March 2009
Volume 10
Number 1

The VA NEPHRON-D study (NCT00555217) may

eventually provide more definitive data on the
effect of the combination of an ACE-I and an ARB
on the progression of kidney disease.31 This
Department of Veterans Affairs-sponsored trial,
which is open for recruitment, will enrol patients
with type 2 diabetes, an estimated glomerular
filtration rate (GFR) of 30 to <90 ml/min/1.73 m2,
and albuminuria >300 mg/g creatinine. Patients
will receive open-label losartan 100 mg in combination with blinded lisinopril 40 mg or placebo
for up to 5 years. The primary study end-point
will be a composite of reduction in estimated
GFR of >50% in patients with baseline estimated

GFR <60 ml/min/1.73 m2, reduction in estimated

GFR of 30 ml/min/1.73 m2 in patients with baseline estimated GFR ? 60 ml/min/1.73 m2, progression to end-stage renal disease, or death.

Emergence of DRIs
With the recent development of DRIs, there is
now the possibility of inhibiting RAAS at its point
of activation (figure 1),32 while simultaneously
abrogating the stimulation of plasma renin activity (PRA) that accompanies the use of ACE-Is and
ARBs. This approach appears to be a particularly
attractive method for treating hypertension.
Additionally, two recent studies have established
that a DRI (aliskiren) can be combined with an
ACE-I33 or an ARB.34 In both studies, the combination of these agents produced a more profound
decrement in blood pressure compared with
monotherapy. Specifically, the combination of
aliskiren 300 mg plus ramipril 10 mg resulted in
a greater lowering of mean sitting diastolic blood
pressure than did monotherapy with either drug
(p=0.004),33 whereas administration of aliskiren
300 mg with valsartan 320 mg produced significant decrement in all blood pressure parameters
versus monotherapy with either drug (p<0.001).34
Additionally, aliskiren monotherapy reduced PRA
by 66%33 and 73%.34 In combination with ramipril
or valsartan, PRA was reduced by 48%33 and
44%,34 respectively (p<0.0001 for all values).

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An exploratory study investigated the time course
of the antiproteinuric and antihypertensive effects
of direct renin inhibition by aliskiren in 15 evaluable patients with type 2 diabetes and microalbuminuria or macroalbuminuria.35 After a 4-week
washout of previous antihypertensive medications,
patients received aliskiren 300 mg and furosemide
daily for 28 days, followed by a 4-week withdrawal period. After initiation of treatment with
aliskiren, there was a progressive reduction from
baseline in urinary albumin/creatinine ratio
(UACR): 17% after 2 to 4 days of treatment
(p=0.04), 31% after 8 to 10 days (p<0.001), and
44% after 2628 days (p<0.001). Mean 24-hour
systolic blood pressure was significantly lower
than baseline after 7, 14, and 28 days of treatment.
Mean 24-hour diastolic blood pressure was not
significantly different from baseline during the
treatment period, but the baseline diastolic blood
pressure was low (75 mmHg). Importantly, there
was no significant correlation between the relative
change from baseline in UACR and in 24-hour
blood pressure (r=0.298, p=0.347). In addition, the
time course of changes in UACR and 24-hour
blood pressure was not concordant. Significant
changes in UACR occurred earlier (days 24) than
changes in 24-hour systolic blood pressure (day
7), and, over the duration of treatment with
aliskiren, there was a progressive reduction from
baseline in UACR but not blood pressure. Findings
of this exploratory study suggest that the antiproteinuric effect of aliskiren is, at least in part, blood
pressure independent.

Journal of
the ReninAngiotensinAldosterone
System
(Including other
Peptidergic systems)
March 2009
Volume 10
Number 1

The AVOID trial was a randomised, double-blind,

placebo-controlled study that enrolled 599 hypertensive patients with type 2 diabetes and nephropathy.36 After a 12- to 14-week, open-label
phase of treatment with losartan 100 mg, patients
were randomly assigned to receive aliskiren
(increasing from 150 to 300 mg) or placebo. The
primary end-point was UACR at 24 weeks. Despite
marginal differences in reductions in blood pressure (systolic, 2 mmHg lower [p=0.07], and diastolic, 1 mm Hg lower [p=0.08], in patients who
received aliskiren), the aliskiren group had a 20%
greater reduction in UACR compared with the
losartan plus placebo group (95% CI, 930;
p<0.001). Whether a comparable antiproteinuric
effect could have been obtained by increasing the
dose of losartan to 200 mg was not explored.
Aliskiren was well tolerated, but there was a
higher incidence of hyperkalemia (6.0 mEq/l) with
aliskiren than with placebo (4.7% vs. 1.7%, respectively; p=0.06). Hyperkalaemia was transient, and
none of the aliskiren-treated patients discontinued
the study drug. This study showed that the addition of aliskiren provided an incremental antiproteinuric effect that appeared to be independent of

blood pressure lowering in hypertensive diabetic

patients who had residual proteinuria despite
treatment with an ARB. Further studies on the
effect of DRIs on the progression of renal disease
are eagerly awaited.
Conclusion
Increasing evidence indicates the inhibition of
RAAS may exert a renoprotective effect that is independent of its effect on blood pressure reduction.
Many studies that have used an end-point of proteinuria as a surrogate for renal protection have
compared the effects of a single blockade of RAAS
using an ACE-I or an ARB with a combined blockade using both an ACE-I and an ARB. Although
some of these studies had methodological limitations, the results of most individual studies and two
meta-analyses suggest that combining an ACE-I and
an ARB may provide an antiproteinuric effect superior to that of monotherapy with either type of
agent. It remains uncertain whether this effect is
limited to conventional doses of ACE-Is or ARBs, or
whether it also pertains to doses that exceed those
approved for the treatment of hypertension. Available
data suggest that the beneficial effect achieved with
combination therapy derives from the more prolonged and complete inhibition of RAAS rather than
from a physiologic interaction between an ACE-I
and an ARB.
The renoprotective effects of monotherapy with an
ACE-I or an ARB compared with combination
therapy have been examined more directly in the
COOPERATE and ONTARGET trials. In COOPERATE,
combination therapy with trandolapril and losartan
slowed the progression of nondiabetic renal disease compared with either agent alone, but the
veracity of the data has been questioned. However,
a secondary finding of ONTARGET was that combination therapy significantly increased the risk for
adverse renal outcomes compared with monotherapy with ramipril. Eventually, more definitive
data are expected from the VA NEPHRON-D trial,
in which patients with diabetic nephropathy will
receive losartan monotherapy or losartan/lisinopril
combination therapy.
Data from the AVOID trial suggest that the addition of aliskiren to an ARB provides an antiproteinuric effect additional to that of the ARB alone.
In AVOID, combination therapy with aliskiren
and losartan resulted in a 20% greater decrease in
UACR than losartan monotherapy, an effect independent of blood pressure reduction.
Given the methodological limitations of existing
studies, additional investigation is warranted. These
trials should examine the efficacy and safety of

SAGE Publications 2009 Los Angeles, London, New Delhi and Singapore

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Review
multiple doses of RAAS inhibitors, making it possible to differentiate more clearly between the
renoprotective and antihypertensive effects of RAAS
blockade, and to use end-points that demonstrate
renal protection more robustly than does the surrogate end-point of proteinuria.
References

Journal of
the ReninAngiotensinAldosterone
System
(Including other
Peptidergic systems)
March 2009
Volume 10
Number 1

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