Journal of Renin-Angiotensin-Aldosterone
The online version of this article can be found at:
2012 13: 118 originally published online 8 August 2011Journal of Renin-Angiotensin-Aldosterone System
Frederik Persson, Julia B Lewis, Edmund J Lewis, Peter Rossing, Norman K Hollenberg and Parving Hans-Henrik
nephropathy: an AVOID substudy
Impact of aliskiren treatment on urinary aldosterone levels in patients with type 2 diabetes and
can be found at:
Journal of Renin-Angiotensin-Aldosterone System
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1 Steno Diabetes Center, Gentofte, Denmark
2 Vanderbilt University School of Medicine, Nashville, TN, USA
3 Rush University Medical Center, Chicago, IL, USA
4 Brigham and Women’s Hospital and Harvard Medical School, Boston,
5 Department of Medical Endocrinology, Rigshospitalet, University of
6 Faculty of Health Sciences, Aarhus University, Aarhus, Denmark
Frederik Persson, Steno Diabetes Center, Niels Steensensvej 1,
DK-2820 Gentofte, Denmark.
Journal of the Renin-Angiotensin-
13(1) 118 –121
© The Author(s) 2011
Reprints and permission:
Impact of aliskiren treatment on
urinary aldosterone levels in patients
with type 2 diabetes and nephropathy:
an AVOID substudy
Frederik Persson1, Julia B Lewis2, Edmund J Lewis3, Peter Rossing1,
Norman K Hollenberg4 and Hans-Henrik Parving5,6
Introduction: Aldosterone blockade reduces albuminuria in diabetic patients with chronic kidney disease (CKD), and
improves prognosis in chronic heart failure. This study assessed the effects of direct renin inhibition with aliskiren in
combination with losartan and optimal antihypertensive therapy on urinary aldosterone, plasma renin activity (PRA) and
plasma renin concentration (PRC).
Materials and methods: In the AVOID study, 599 patients with type 2 diabetes, hypertension and nephropathy received
6 months aliskiren (150 mg force titrated to 300 mg once daily after 3 months) or placebo added to losartan 100 mg
and optimal antihypertensive therapy. Urinary aldosterone excretion, PRA and PRC were measured at baseline and after
24 weeks in a prespecified subset of 133 patients.
Results: Aliskiren added to losartan provided reductions from baseline in urinary aldosterone compared with adding
placebo (−24% vs. −4%, p = 0.017) at week 24. There was no significant difference between the aliskiren and placebo
groups in the proportion of patients with aldosterone breakthrough (aliskiren 35%, placebo 46%, p = 0.199). Aliskiren
treatment reduced PRA by 90% at 24 weeks and increased PRC by 328%.
Conclusions: Adding aliskiren to recommended renoprotective treatment with losartan and optimal antihypertensive
therapy provided significant reductions in urinary aldosterone excretion which may attenuate decline in kidney function.
Albuminuria, aldosterone, aliskiren, diabetes, nephropathy, renin inhibition
Aldosterone has well described deleterious effects in
several key organs.1 Treatment directed towards the
aldosterone receptor has a potential for treating CKD.2–4
After initiation of renin–angiotensin–aldosterone system
(RAAS) blocking treatment with angiotensin-converting
enzyme (ACE) inhibitors or angiotensin receptor blockers
(ARBs), plasma aldosterone levels normally decrease, but
in 30–40% of patients, plasma aldosterone levels return to
pretreatment levels or higher during ongoing treatment.
This phenomenon, called ‘aldosterone breakthrough’,5 is
associated with a larger decline in renal function,5,6 and
may constitute a potential point of intervention with miner-
alocorticoid antagonists in patients otherwise treated with
maximal renoprotective therapy.
Direct renin inhibition bears interesting possibilities as
treatment with aliskiren, the first available drug in this class,
blocks the RAAS at the first rate-limiting step resulting in
very low levels of angiotensin II. Although plasma renin
concentration rises accordingly, aliskiren effectively binds to
renin and plasma renin activity is decreased.7 The AVOID
study8 is the largest study so far with aliskiren in patients with
type 2 diabetes and nephropathy. The main result showed
that aliskiren 300 mg once daily added to recommended
Persson et al.
renoprotective treatment with the ARB losartan 100 mg once
daily and optimal antihypertensive treatment reduced albu-
minuria by 20% compared with placebo over 6 months.
Samples were taken from a prespecified subset of 133
patients, and were analysed for urinary aldosterone levels,
plasma renin activity (PRA) and plasma renin concentration
(PRC) to investigate the impact of combined RAAS block-
ade on urinary aldosterone and plasma renin levels.
Materials and methods
In a randomized, double blind, placebo-controlled study
(AVOID), we evaluated the renoprotective effect of
aliskiren in 599 hypertensive patients with type 2 diabetes
and nephropathy. The methods have been described in
detail in the main publication.8
In a subset of patients (n = 133) biomarkers were ana-
lysed. In plasma samples we measured PRC using CISbio
Renin III kits (Bagnols/Cèze, France) and PRA using
DiaSorin RIA kits (Minneapolis, USA). Urinary aldoster-
one was measured using Siemens RIA Coat-a-Count
(Tarrytown, USA). Urinary aldosterone excretion over 24
hours was chosen over plasma aldosterone sampling, as the
urinary analysis reflects the mean aldosterone level better
than random plasma samples due to diurnal variation in
plasma aldosterone levels.
Changes from baseline in log-transformed biomarkers
were analysed using analysis of covariance (ANCOVA)
models with baseline log-transformed biomarker as a
covariate, and treatment, region and baseline albuminuria
classification as factors. To assess the frequency of aldos-
terone breakthrough in the two treatment groups, responder
analysis evaluated the proportion of patients with a reduc-
tion from baseline (i.e. >0% reduction) in urinary aldoster-
one; between-treatment comparisons were made by χ2 test.
Characteristics of the subset patients (Table 1) were not sig-
nificantly different from patients in the original AVOID study,
but the difference between the two groups was less than in the
main study. Reduction in urinary albumin creatinine ratio
(UACR) over the 24-week study period in this subset of
patients was 22% and 9% for aliskiren and placebo groups,
respectively (NS). Compared to placebo, adding aliskiren
300 mg reduced urinary aldosterone levels by 20% after 24
weeks of treatment (p = 0.017) (Figure 1). PRA was reduced
93% from baseline to week 24 by aliskiren (p < 0.001).
Aliskiren treatment increased PRC by 328% from baseline,
while placebo group PRC was reduced by 17% (between-
treatment p < 0.001) (Table 2). Mean systolic BP was reduced
by 0.5 mmHg in the aliskiren group, and increased by
1.9 mmHg in the placebo group (p = 0.33). Mean diastolic
BP was reduced by 3.1 mmHg in the aliskiren group and
increased by 0.4 mmHg in the placebo group (p = 0.013).
Table 1. Baseline characteristics of 133 patients included in the
substudy of the AVOID study
Male gender, n(%)
Body mass index, kg/m2
≥ 30 kg/m2, n(%)
Baseline eGFR, n(%)
<60 mL/min/1.73 m2
≥60 mL/min/1.73 m2
Data are presented as mean±SD, unless otherwise stated. aData are
shown as geometric means (95% confidence interval). DBP: diastolic
blood pressure, eGFR: estimated glomerular filtration rate, SBP: systolic
blood pressure, UACR: urinary albumin creatinine ratio, UAER: urinary
albumin excretion rate.
Table 2. Results in urinary aldosterone, PRA and PRC according to treatment group
Baseline Week 24Change
Baseline Week 24Change
15.8 12.0 –24%
2.2 0.2 3.2 2.6
PRA: plasma renin activity, PRC: plasma renin concentration.
Journal of the Renin-Angiotensin-Aldosterone System 13(1)
The proportion of patients with a reduction from base-
line in urinary aldosterone (no signs of aldosterone break-
through) was numerically higher in the aliskiren group
relative to the placebo group (65% in the aliskiren group
compared to 54% in the placebo group although this was
not statistically significant, p = 0.199). There was no differ-
ence between the two groups in side effect frequency.
Renin inhibition added to recommended renoprotective
treatment including losartan 100 mg once daily reduced uri-
nary aldosterone levels by 24% during 24 weeks of treat-
ment. This extends findings from a smaller study that found
a nonsignificant 23% difference between plasma aldoster-
one levels in patients treated with irbesartan combined with
aliskiren as compared to irbesartan monotherapy.9
We found a higher proportion of patients with a reduction
in urinary aldosterone levels in the aliskiren group as com-
pared to placebo. The proportion of patients with an increase
in urinary aldosterone levels (aldosterone breakthrough) was
46% in the placebo group and 35% in the aliskiren group.
Schjoedt et al.10 have reported dual RAAS blockade leading
to a decrease in plasma aldosterone in 36 of 51 (70%) patients
with type 1 diabetes and diabetic nephropathy.
In this subpopulation of the AVOID study the changes in
albuminuria were different from the main study, suggesting
less power and limiting the conclusions to be made.
The changes in PRA and PRC correspond to previous
studies.9,11 It is, however, unknown if the low activity of the
renin enzyme is responsible for the reduction in urinary
Aldosterone is known to have numerous deleterious
effects on the kidney.12 Renin inhibition added to RAAS
blockade is currently being investigated in the ALTITUDE
study13 and this will provide further data on this important
The study was funded by Novartis Pharma AG.
Conflict of interest
Dr Persson reports having received lecture fees from Novartis
and having equity interest in NovoNordisk. Dr Rossing reports
having received lecture fees from Novartis and Boehringer
Ingelheim; a research grant from Novartis; having served as a
consultant for Merck; and having equity interest in NovoNordisk.
Dr E Lewis reports having received grant support from Keryx
Biopharmaceuticals. Dr JB Lewis reports having served as a con-
sultant for Merck and Novartis and having received grant support
from Keryx Biopharmaceuticals and the National Institute of
Health. Dr Hollenberg reports having received grant support
from Novartis and Merck. Dr Parving reports having served as a
consultant for Novartis, Merck, Pfizer and Sanofi-Aventis; hav-
ing equity interest in Merck and NovoNordisk; having received
lecture fees from Novartis, Merck, Pfizer and Sanofi-Aventis;
and having received grant support from Novartis, AstraZeneca
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Figure 1. Geometric mean change (%) from baseline to week
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