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D / Diabetes type 2 with proteinuria
D / Diabetes type 2 with CV complications
E / hypertension with other endocrine diseases
Determinants and Changes Associated with Aldosterone
Breakthrough after Angiotensin II Receptor Blockade in Patients
with Type 2 Diabetes with Overt Nephropathy
Olivier Moranne*,†, George Bakris‡, Coraline Fafin†, Guillaume Favre*,§ Christian Pradier†,
Vincent L.M. Esnault*,§
CJASN October 07, 2013 8): (10) 1694-1701
+ Author Affiliations
Nephrology and
Epidemiology Departments, Nice University Hospital, Nice, France;
ASH Comprehensive Hypertension Center, University of Chicago, Chicago, Illinois;
4. §Institut National de la Santé et de la Recherche Médicale U1081, Nice SophiaAntipolis University, Nice, France
Prof. Vincent L. M. Esnault, Nephrology Department, Pasteur Hospital, 30 av. de la Voie
Romaine, 06002 Nice, France. Email: [email protected]
Background and objectives
Inhibition of the renin-angiotensin-aldosterone system decreases proteinuria and slows
estimated GFR decline in patients with type 2 diabetes mellitus with overt nephropathy.
Serum aldosterone levels may increase during renin-angiotensin-aldosterone system
blockade. The determinants and consequences of this aldosterone breakthrough remain
Design, setting, participants, & measurements
This study examined the incidence, determinants, and changes associated with aldosterone
breakthrough in a posthoc analysis of a randomized study that compared the effect of two
angiotensin II receptor blockers in patients with type 2 diabetes mellitus with overt
Of 567 of 860 participants included in this posthoc analysis, 28% of participants developed
aldosterone breakthrough, which was defined by an increase greater than 10% over baseline
values of serum aldosterone levels after 1 year of angiotensin II receptor blocker treatment.
Factors independently associated with aldosterone breakthrough at 1 year were lower serum
aldosterone and potassium levels at baseline, higher decreases in sodium intake, systolic
BP, and estimated GFR from baseline to 1 year, and use of losartan versus telmisartan.
Aldosterone breakthrough at 6 months was not sustained at 1 year in 69% of cases, and it
did not predict estimated GFR decrease and proteinuria increase between 6 months and 1
Aldosterone breakthrough is a frequent event 1 year after initiating renin-angiotensinaldosterone system blockade, particularly in participants exposed to intensive lowering of BP
with sodium depletion and short-acting angiotensin II receptor blockers. Short-term serum
aldosterone level increases at 6 months are not associated with negative kidney outcomes
between 6 months and 1 year
Inhibition of the renin-angiotensin-aldosterone system (RAAS), either through angiotensinconverting enzyme inhibitors (ACEIs) in patients with diabetes type 1 and nondiabetics or
angiotensin II receptor blockers (ARBs) in patients with type 2 diabetes mellitus (T2DM) ,
decreases proteinuria and slows down the decline in GFR in patients with proteinuria.
Indeed, residual proteinuria is a predictor of progression to renal failure . However, despite
RAAS blockade, many patients display high residual proteinuria levels and develop ESRD . It
is possible that RAAS blockade strategies may be suboptimal, because serum aldosterone
levels may increase during RAAS blockade with all ACEIs or ARBs tested so far.
The incidence of this aldosterone breakthrough is up to 53% after 1 year of RAAS blockade,
depending on the definition used . Aldosterone breakthrough is usually defined by the
increase in serum aldosterone levels compared with baseline levels before RAAS blockade
and ranges from 40% to 53% at 1 year
Aldosterone breakthrough may be associated with cardiovascular and renal morbidity.
Indeed, it may reverse the beneficial effects of an ACEI on left ventricular hypertrophy, and
the improvement in functional capacity noted in patients with congestive heart failure treated
with ACEI is decreased when aldosterone breakthrough is present. High serum aldosterone
levels are an independent risk factor for in-hospital cardiovascular/renal morbidity or mortality
after myocardial infarction. In patients with diabetic or IgA nephropathies, aldosterone
breakthrough is associated with higher levels of proteinuria levels, and progression to renal
failure may be more rapid in diabetic patients with aldosterone breakthrough. Furthermore,
serum aldosterone has been reported to induce inflammation and fibrosis in experimental
animals and therefore, could accelerate renal damage.
From the study, it can be concluded that aldosterone breakthrough is a frequent event in
participants with T2DM with overt nephropathy after the initiation of ARB treatment, and it
may be favored by baseline hypervolemia, subsequent greater decrease in SBP, sodium
intake, and eGFR during follow-up, and use of a short-acting ARB. Long-term studies are
required to test whether prevention of aldosterone breakthrough by cautious dual ACEI/ARB
blockade in specific patient population or aldosterone inhibitors would lead to improved
Pr. Jacques CHANARD
Professor of Nephrology
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