Impact of aliskiren treatment on urinary aldosterone levels in patients with type 2 diabetes and nephropathy: an AVOID substudy.
ABSTRACT 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).
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.
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%.
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.
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ABSTRACT: We have reported observing aldosterone breakthrough in the course of relatively long-term treatment with renin-angiotensin (RA) system inhibitors, where the plasma aldosterone concentration (PAC) increased following an initial decrease. Aldosterone breakthrough has the potential to eliminate the organ-protective effects of RA system inhibitors. We therefore conducted a study in essential hypertensive patients to determine whether aldosterone breakthrough occurred during treatment with the direct renin inhibitor (DRI) aliskiren and to ascertain its clinical significance. The study included 40 essential hypertensive patients (18 men and 22 women) who had been treated for 12 months with aliskiren. Aliskiren significantly decreased blood pressure and plasma renin activity (PRA). The PAC was also decreased significantly at 3 and 6 months; however, the significant difference disappeared after 12 months. Aldosterone breakthrough was observed in 22 of the subjects (55%). Urinary albumin excretion differed depending on whether breakthrough occurred. For the subjects in whom aldosterone breakthrough was observed, eplerenone was added. A significant decrease in urinary albumin excretion was observed after 1 month, independent of changes in blood pressure. In conclusion, this study demonstrated that aldosterone breakthrough occurs in some patients undergoing DRI therapy. Aldosterone breakthrough affects the drug's ability to improve urinary albumin excretion, and combining a mineralocorticoid receptor antagonist with the DRI may be useful for decreasing urinary albumin excretion. When the objective is organ protection in hypertensive patients, a two-pronged approach using combination therapy to inhibit both the RA system and aldosterone may be highly effective.Hypertension Research advance online publication, 18 July 2013; doi:10.1038/hr.2013.74.Hypertension Research 07/2013; · 2.79 Impact Factor
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ABSTRACT: Historically, urinary aldosterone level measurement was a commonly employed confirmatory test to detect primary aldosteronism (PA). However, 24-h urine collection is inconvenient and cumbersome. We hypothesized that random urinary aldosterone measurements with correction for creatinine concentration might be comparable to 24-h urinary aldosterone levels (Uald-24 h) in the diagnosis of PA. The non-concurrent prospective study was conducted between June 2006 and March 2008 in patients admitted for confirmation of aldosteronism by salt loading test. A 24-h urine sample, which was collected during hospitalization on the day before saline infusion testing after restoration of serum hypokalemia, was collected from all subjects. Moreover, participants were asked to collect a first bladder voiding random urine sample during clinic visits. Uald-24 h and the random urinary aldosterone-to-creatinine ratio (UACR) were calculated accordingly. A total of 102 PA patients (71 patients diagnosed of aldosterone-producing adenoma, 31 with idiopathic hyperaldosteronism) and 65 patients with EH were enrolled. The receiver operating characteristic curve showed comparable areas under the curves of UACR and Uald-24 h. The Bland-Altman plot showed mean bias but no obvious heteroscedasticity between the two tests. When using random UACR >3.0 ng/mg creatinine as the cutoff value, we obtained a specificity of 90.6% to confirm PA from essential hypertension. Our study reinforce that the diagnostic accuracy of random UACR was comparable to that of Uald-24 h in PA patients. With the quickness and simplicity of the UACR method and its equivalence to Uald-24 h, this assay could be a good alternative diagnostic tool for PA confirmation.PLoS ONE 06/2013; 8(6):67417-. · 3.53 Impact Factor
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ABSTRACT: Abstract Background: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Renin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of DKD with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) being the mainstay of treatment. Systemic RAAS activity has been implicated in the pathogenesis of DKD, but lately interest has shifted to intrarenal RAAS effect. With the discovery of the (pro)renin receptor and ACE independent pathways of angiotensin II production, our understanding of role of renin in end organ damage has improved significantly. Summary: We summarize our current understanding of ACE dependent and independent pathways in the development of DKD and the preclinical models demonstrating renal effects of direct renin inhibitors (DRIs). We then review clinical studies and trials performed so far evaluating the efficacy of aliskiren on renal outcomes and safety in DKD. Key message: At present, there is little evidence for renal benefit of aliskiren in DKD beyond that offered by ACEIs or ARBs. Combining aliskiren with ACEI or ARB in DKD did not significantly improve renal outcomes in comparison with ACEI or ARB monotherapy in clinical trials. Slightly more adverse events including hyperkalemia, acute kidney injury and hypotension were observed in the combination therapy as compared to the monotherapy. Thus, current evidence suggests that aliskiren, because of its antihypertensive and antiproteinuric effects, maybe used as monotherapy in DKD and considered an equivalent alternative to ACEIs or ARBs. Careful monitoring for renal adverse effects would allow safe clinical use of DRI.Renal Failure 03/2014; · 0.94 Impact Factor
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
BaselineWeek 24 Change
15.8 12.0 –24%
18.6 17.9 –4%
2.2 0.2 3.2 2.6
PRC, ng/L 26.988.1 37.331.0
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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