NDT Advance Access originally published online on October 5, 2006
Nephrology Dialysis Transplantation 2007 22(1):5-8; doi:10.1093/ndt/gfl549
© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Secondary rise of albuminuria under AT1-receptor blockade—what is the potential role of aldosterone escape?
Lars Christian Rump
Klinikum der Ruhr-Universität Bochum, Marienhospital Herne, Bochum, Germany
Correspondence and offprint requests to: Prof. Dr L. C. Rump, Klinikum der Ruhr-Universität Bochum, Medizinische Klinik I, Marienhospital Herne, Hölkeskampring 40, 44625 Herne, Germany. Email: christian.rump{at}ruhr-uni-bochum.de
Keywords: ACE inhibition; albuminuria; aldosterone escape; angiotensin II; AT1-receptor blockade
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Introduction
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Inhibition of the renin–angiotensin system is the recommended
standard therapeutic regimen in chronic kidney disease. The
reasons for this choice are obvious. On the one hand angiotensin-converting
enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs)
are almost indispensable to reach target blood pressure in this
group of patients [
1]. On the other hand they cause blood pressure
independent reductions of proteinuria which ameliorates renal
disease progression [
2]. Moreover, the presence of glomerular
proteinuria is indicative for high cardiovascular risk. It is
now generally accepted that the antiproteinuric response to
inhibitors of the RAS predicts not only progression, but also
cardiovascular outcome in chronic renal failure [
3]. Those patients
with the largest reduction of proteinuria have the greatest
cardiovascular benefit. Unfortunately—after an initial
decrease—in many patients proteinura rises again under
continued ACE inhibitor therapy. Such secondary increase in
albuminiuria has even occured in non-renal patients treated
with an ARB in the large LIFE study [
4]. This editorial discusses
the evidence that the aldosterone escape phenomenon is responsible
for the secondary rise of proteinuria under RAS blockade and
presents the rationale for blockade of the mineralocorticoid
receptor in the event.
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Aldosterone and proteinuria
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Since the description of Conn in 1964 of 145 patients with primary
hyperaldosteronism it is known that high plasma aldosterone
levels are in most cases associated with proteinuria [
5]. However,
for a long time this symptom has been attributed to the deleterious
effects of high blood pressure rather than direct effects of
aldosterone on glomerular permselectivity. Today, there is clear
evidence that aldosterone causes direct and blood pressure independent
renal injury and proteinuria. In the remnant kidney model which
is characterized by high plasma aldosterone levels, removal
of the adrenals reduces proteinuria [
6]. Furthermore, aldosterone
infusion induces proteinuria even in the presence of ACE inhibitors
and ARBs [
7]. It is unknown to what extent these actions of
aldosterone are mediated via genomic or non-genomic effects.
Certainly several non-genomic effects of aldosterone have been
reported which may contribute to its pro-proteinuric action
[
8]. The effects of aldosterone on the kidney include haemodynamic
and non-haemodynamic mechanisms. Concerning the latter, aldosterone
induces renal inflammation and fibrosis [
9] via several pathomechanisms:
increased Ca
2+-influx into renal cells [
10], activation of MAP
kinase [
11], stimulation of PAI-1 [
12], formation of reactive
oxygen species [
13] and expression of TGF-ß [
14].
Moreover, classical pharmacological experiments have demonstrated
that aldosterone constricts renal efferent arterioles more potently
than afferent arterioles [
15] via endothelium-dependent mechanisms
[
16]. Furthermore, aldosterone potentiates Ang II-mediated signaling
in smooth muscle cells. Differential vasoconstriction of efferent
vs afferent arterioles as well as potentiation of the vasoconstrictor
action of Ang II may contribute to hyperfiltration and proteinuria
[
17]. It is interesting to note that albuminuria is present
even in young only moderately hypertensive patients with glucocorticoid
remediable aldosteronism [
18]. However, it is not well understood
to what extent receptor-mediated molecular pathways are involved—an
important point for the indication to use blockers of the mineralocorticoid
receptor. For example, only some of the described renal effects
of aldosterone effects are blocked by receptor antagonists,
whilst others are not.
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What is known about aldosterone escape under RAS blockade?
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In a physiological setting, adrenal aldosterone formation and
release is regulated mainly by Ang II (
Figure 1). It is well
established that ACE inhibitor therapy causes an initial decrease
in Ang II levels, followed by a sustained secondary increase
back to pretreatment levels. The most favoured explanation is
that non-ACE enzymes are capable of cleaving Ang I to Ang II
[
19]. It is therefore tempting to consider that aldosterone
escape is merely a consequence of Ang II escape. However, this
assumption would not explain why aldosterone escape is a problem
of ARB therapy as well. If all AT1-receptors are blocked, all
stimulatory effects of Ang II on adrenal aldosterone secretion
should be abrogated. Nevertheless, aldosterone escape has been
documented even under ARB therapy. For instance, in the RESOLVD
study in patients with heart failure, after 17 weeks of candesartan
treatment, plasma aldosterone levels had decreased markedly,
yet increased to pretreatment levels or even higher after prolonged
therapy for 43 weeks [
20]. In contrast, in another large trial
(Val-HeFT) a sustained reduction of aldosterone in response
to the ARB valsartan was reported for patients with chronic
heart failure over a period of 24 months [
21], but the interpretation
of the data has been challenged [
22]. There was indeed a decrease
of aldosterone levels by 17.4% after 24 months compared with
baseline, but the documented continuous increase in aldosterone
levels between 4 and 24 months seems to indicate at least some
degree of aldosterone escape. How can one explain aldosterone
escape under AT1-receptor blockade? Apart from Ang II, several
additional factors are known to stimulate adrenal aldosterone
synthesis and release
in vitro [
23] for instance bradykinin,
endothelin, noradrenaline and parathyroid hormone. A physiological
role of these agonists is uncertain, however. In addition to
Ang II, potassium (K
+) and corticotrophin (ACTH), have undoubted
physiological significance and these stimuli may even synergize
with Ang II. The increase in plasma potassium levels may be
one reason for aldosterone escape during ARB treatment. Atrial
natriuretic peptide inhibits adrenal aldosterone production
[
24]. Since at least in chronic heart failure ANP levels decrease
during ARB therapy, release of aldosterone secretion from inhibition
by ANP may be another potential interpretation. On the other
hand experimental evidence in stroke-prone hypertensive rats
suggests that aldosterone escape during ARB treatment is mediated
by an AT2-receptor-dependent mechanism. Dexamethasone and the
AT2-receptor antagonist PD123319, but not high doses of candesartan,
reduced plasma aldosterone levels in these animals [
25]. Another
unresolved question is whether the aldosterone which is responsible
for the deleterious effect on the kidney and other cardiovascular
organs is derived from circulating blood or produced locally
[
26]. In adrenalectomized diabetic rat kidneys, Xue
et al. [
27]
found evidence of local aldosterone production. In contrast,
in transgenic rats over expressing both the human renin and
angiotensinogen genes. Fiebeler
et al. [
28] were unable to show
significant local aldosterone formation in cardiac tissue when
these animals had been subjected to adrenalectomy
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Fig. 1. Mechanisms of aldosterone escape during AT1-receptor blockade or ACE-inhibition. During AT1-receptor blockade Ang II levels increase. Experimental evidence suggests that in this situation Ang II activates adrenal AT2-receptors to stimulate aldosterone synthesis and release. During ACE inhibition non-ACE enzymes are capable of cleaving Ang I to Ang II, which stimulates adrenal aldosterone release via activation of AT1-receptors. Potassium (K+), which increases during RAS blockade, induces aldosterone release. Aldosterone has a direct blood pressure independent pro-proteinuric effect on the kidney. For more detailed information see text and for other regulatory mechanisms* of adrenal aldosterone release see review [23].
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Clinical considerations and outlook
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When aldosterone receptor antagonists are administered on top
of either ACE inhibitors or ARBs, a further decrease of proteinuria
is commonly observed. This was first shown by Chrysostomou
et al. [
29] for the combination enalapril plus spironolactone.
After 1 year of enalapril treatment, eight patients with various
chronic kidney diseases still had an average proteinuria of
3.81 g/24 h which was reduced to 1.75 g/24 h after 4 weeks of
add-on 25 mg spironolactone [
29]. Similar results were obtained
subsequently by other investigators. A causal role of aldosterone
is suggested by the observation in patients with diabetic nephropathy
that those with aldosterone escape have more pronounced proteinuria
than those without [
30]. In addition the higher the plasma aldosterone
level, the greater the antiproteinuric response to aldosterone
antagonists [
31]. Moreover, patients with aldosterone escape
have a faster decline of renal function. Schjoedt and coworkers
[
32] treated 63 hypertensive type 1 diabetics for 35 months
with 100 mg losartan. The rate of loss of GFR was 5 ml/min/year
in patients with aldosterone escape (
n = 26) and 2.4 ml/min/year
in those without (
n = 37). Taken together, the presented evidence
favours the idea that aldosterone escape during treatment with
either ACE inhibitors or ARBs results in a secondary rise of
glomerular proteinuria. There remain open questions: in view
of potential adverse events, e.g. hyperkalaemia, which patients
can safely be treated with aldosterone antagonists? Bianchi
et al. [
31] demonstrated that patients with a GFR < 60 ml/min
are more likely than those with a GFR > 60 ml/min to develop
hyperkalaemia. Is it justified to use ‘prophylactically’
a combination of RAS blockade with low dose aldosterone antagonists
in all patients with proteinuria >0.5 g/day as suggested
[
33] or only in patients with documented aldosterone escape?
Is there a cut-off for aldosterone levels justifying combination
therapy? The author believes that at present neither prophylatic
use of aldosterone antagonists nor definite cut-off levels of
plasma aldosterone for initiating aldosterone antagonist therapy
can be recommended. It is the author's opinion that any patient
with increasing aldosterone levels during ARB or ACE inhibitor
therapy has aldosterone escape to an extent which might legitimate
add-on of an aldosterone receptor blocker. However, online monitoring
of aldosterone levels before and after initiating ARB or ACE
inhibitor therapy appears inappropriate in daily practice. Therefore,
the following recommendation seems feasible. In compliant patients
with a GFR >30 ml/min and proteinuria >1 g/day after 6
months of treatment with an ARB or ACE inhibitor add-on of 25
mg spironolactone should be considered. In a recent study by
Chrysostomou
et al. [
34], the combination of 5 mg ramipril with
25 mg spironolactone was more effective in reducing proteinuria
than the combination of 5 mg ramipril with 150 mg irbesartan.
Nevertheless, a careful eye on serum potassium and creatinine
is mandatory! Finally, it will be interesting to see whether
renin inhibition by aliskiren will overcome the problem of aldosterone
escape in the future.
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Acknowledgement
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The drawing of kidney and adrenal used in
Figure 1 was kindly
provided by Prof. Nies, Marienhospital Osnabrück.
Conflict of interest statement. None declared.
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Received for publication: 8. 8.06
Accepted in revised form: 16. 8.06
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Introduction
Aldosterone and proteinuria