Nephrol Dial Transplant (2009) 1 of 4

doi: 10.1093/ndt/gfp206
Editorial Comment
Aldosterone, a vasculotoxic agentnovel functions for
an old hormone
Eberhard Ritz
1
and Andreas Tomaschitz
2
1
Department of Internal Medicine, Klinikum der Universit at Heidelberg, Nierenzentrum, Im Neuenheimer Feld 162, 69120
Heidelberg, Germany and
2
Division of Endocrinology and Nuclear Medicine, Department of Internal Medicine,
Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
Correspondence and offprint requests to: Prof. Dr. Dr. med. h.c. mult. Eberhard Ritz; E-mail: Prof.E.Ritz@t-online.de
Keywords: aldosterone; hyperaldosteronism; hypertension;
inflammation; proteinuria
Aldosterone and blood pressurebeyond Conn
syndrome
In 1955, the syndrome of primary aldosteronism was de-
scribed by and subsequently named after J. W. Conn [1].
It was defined as high aldosterone concentrations in the
presence of adrenal adenoma or bilateral hyperplasia. Re-
cently, the definition of the syndrome has been expanded
and theclaimed or realfrequency has risen sharply [2].
An animated discussion is going on whether we are really
dealing with a true rise in the frequency of primary aldos-
teronism as originally defined.
New data allow a more sophisticated and broader in-
terpretation of the role of aldosterone. In the Framingham
offspring study, it had been documented that the frequency
of a rise in blood pressure and the incidence of hyper-
tension increase progressively from the first to the fourth
quartile of serum aldosterone concentrations [3]. This led
recently to the comment whether primary aldosteronism
is as widespread as some believe may not be as relevant
as whether the commonly prevailing level of aldosterone
is too high for the amount of sodium we consume [4]. In
line with the idea that aldosterone plays a more general
role in the genesis of hypertension, it was also stated that
aldosterone . . . contributes to the development of hyper-
tension . . . more than even the most generous estimates for
the prevalence of primary hyperaldosteronism [4]. This
interpretation finds support in some recent experimental
data. Makhanova [5] created salt-sensitive blood pressure
in mice by increasing the expression of aldosterone syn-
thase by manipulating the untranslated regions of aldos-
terone synthase gene in mice, raising aldosterone synthase
mRNA by a factor of 1.5. On low salt, such mice had nor-
mal blood pressure but less activation of RAS than wild
type. On high salt, however, blood pressure was higher by
10 mmHg, accompanied by hypokalaemia and increased ex-
pression of collecting duct sodium channel (ENaC). Along
these lines, a study in humans [6] found a correlation be-
tween an aldosterone synthase polymorphism(344T/C) and
aldosterone excretion as well as hypertension; this obser-
vation has recently been confirmed by one study [7] but
not by another one [8]. It is likely that the blood pressure-
raising effect of aldosterone is not only the result of na-
triuresis and sodium balance; in anuric dialysis patients,
50 mg spironolactone lowered systolic blood pressure by
11mmHg, remarkably without a change in serumpotassium
and presumably as a result of a direct vascular effect [9].
Activation of the mineralocorticoid
receptorbeyond aldosterone
When I.S. Edelman characterized the mineralocorticoid
receptor, he had difficulties to publish the finding be-
cause the receptor was orders of magnitudes more sen-
sitive to cortisol than to aldosterone. This paradox has
subsequently been clarified by the demonstration of pre-
receptor metabolism, i.e. local conversion at the receptor
site of cortisol to its metabolite cortisone that does not in-
teract with the mineralocorticoid receptor. This conversion
is catalyzed by 11-beta-hydroxysteroid dehydrogenase-2
(11-beta-HSD-2), malfunction of which is associated with
several forms of hypertension, including hypertension of
the elderly [10]. Recent studies concluded that an ancient
steroid receptor had been highjacked by aldosterone after
transition of vertebrates fromthe sea to land life when more
stringent conservation of sodium was required.
More relevant for the recent epidemic of hypertension
associated with high aldosterone concentrations is the ob-
servation that visceral obesity is associated with elevated al-
dosterone [11], mainly because human visceral adipocytes
secrete potent mineralocorticoid-releasing factors [12] pre-
sumably EKODE [epoxy-9keto-10trans-octadecenoic acid]
[13]. This may explain the observation in the Fram-
ingham study that plasma aldosterone concentration was
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2 Nephrol Dial Transplant (2009)
significantly correlated with the risk of onset of the
metabolic syndrome [14]. In an animal model of the
metabolic syndrome, aldosterone caused podocyte in-
jury [15] with proteinuria responsive to treatment with
eplerenone [16] and tempol [17] pointing to a role of oxyda-
tive stress.
Aldosterone actionsbeyond the classical
mineralocorticoid receptor
The classical concept of aldosterone was that aldosterone
synthesized in the adrenal cortex acted in an endocrine
fashion on transport epithelial (distal nephron, colon, sali-
vary glands, sweat gland), promoting vectoral transep-
ithelial Na
+
transport mediated by SGK-1 (serum and
glucocorticoid-inducible kinase).
This concept has now been expanded in two ways. First,
non-genomic effects have been identified mediated by the
interaction of aldosterone with a hypothetical plasma mem-
brane receptor, the time frame of such actions is seconds
(and not hours as necessary for genomic effects), and these
effects are not inhibited by the transcription inhibitor acti-
nomycin D [18].
Second, apart from the classical effects of aldosterone
on transport epithelia, non-classical effects on interstitial
tissues, specifically endothelial cells, fibrocytes, have more
recently been identified as well.
Aldosterone has thus become a hormone not only in-
volved in blood pressure control but also involved in car-
diovascular and renal target organ damage. These past and
novel roles have recently been summarized as the good,
the bad and the ugly [19].
The good: aldosterone causes sodium retention and potas-
siumhomeostasis, thus avoiding hypotension in land-living
species.
The bad: in the presence of high-salt intake, aldosterone
causes persistent hypertension resulting in blood pressure-
dependent target organ damage.
The ugly: in a permissive milieu, also tightly linked to high-
sodium intake, even normal aldosterone concentrations
promote blood pressure-independent target organ damage
caused via inflammatory or pro-fibrotic pathways involving
oxydative stress, activation of NF-kappa-B, AP-1, NADP-
oxydase, ICAM, VCAM and others.
Aldosteroneblood pressure-independent target
organ damage
Amost elegant experiment in human endothelial cell mono-
layer cultures was reported by Oberleithner [20]: when the
extracellular sodium concentration was increased above a
threshold of 135 mmol/mM, endothelial cell stiffness in-
creased in the presence of aldosterone but this could be
prevented by adding the mineralocorticoid receptor antag-
onist eplerenone. Increased endothelial cell stiffness was
mediated by interaction of aldosterone with a hypothetical
plasma membrane receptor. In the presence of high-sodium
concentration, its activation decreased nitric oxygen (NO)
release, thus altering endothelial cells and the neighbouring
vascular smooth muscle cells function causing increased
vascular stiffness and resistance [21]. Acorrelation between
indices of vascular stiffness and aldosterone-to-renin ratios
was for instance found in the Framingham offspring study
[22].
Observations in humans are in line with this pathome-
chanism. For instance, Mahmud [23] showed that in hy-
pertensive patients, blood pressure was similarly lowered
with either spironolactone or a thiazide. While both drugs
reduced blood pressure, only spironolactone but not the
thiazide reduced the pulse wave velocity; this effect was
blood pressure independent, pointing to direct endothe-
lial cell and vascular actions of aldosterone. Such direct
effects have been documented in vessels, in heart tis-
sue [24] and in kidneys [25]. It is somewhat controver-
sial whether ectopic production of aldosterone outside of
the adrenal gland occurs in healthy humans, but it was
documented in the heart of patients with cardiac failure
[26].
Such blood pressure-independent and natriuresis-
independent effects explain the benefit observed with
the effect of non-natriuretic doses of spironolactone or
eplerenone in patients with severe heart failure, i.e. in the
RALES [27] and EPHESUS [28] studies.
Aldosterone and progression of renal disease
In malignant nephrosclerosis of the SHRsp on high salt
[29] or in rats double transgenic for the human renin and an-
giotensinogen genes [30] as well as in a model of malignant
nephrosclerosis [31], manoeuvres such as adrenalectomy or
administration of eplerenone or spironolactone prevented
renal and vascular tissue damage.
Studies in animals with renal failure showed hyperpla-
sia of the zona glomerulosa [32] and a 10-fold increase
in plasma aldosterone [33] of the adrenal gland, while
conversely adrenalectomy reversed proteinuria and struc-
tural lesions in the subtotally nephrectomized rat [34].
The decisive experiment was performed by Greene and
Hostetter [33]: after subtotal nephrectomy, RAS blockade
(ACE inhibitors plus ARB) caused a striking decrease of
proteinuria. Additional administration of aldosterone, how-
ever, increased proteinuria again by a factor of almost 10.
Spironolactone does not only prevent glomerular lesions
[33] but also causes even regression of established glomeru-
losclerosis [35].
In all these studies, animals were on a high-sodium diet
and such adverse effects of aldosterone occur only under
high salt conditions. The importance of salt intake is beau-
tifully illustrated by an Indian tribe in the Amazonas, the
Pima Indians, who live on minimal sodiumintake (natriure-
sis 1 1.5 mmol/day): they have low blood pressure values
(102/62 mmHg) despite serum aldosterone concentrations
above the usual concentration in Conn syndrome (85.6
78 ng/dl [36]. In animal experiments, high-salt environment
is found to be associated with an inflammatory response
(NF-kappa-B), diminished nitric oxide release as well as
inflammatory infiltrates and tissue remodelling [37].
Nephrol Dial Transplant (2009) 3
Against this background, Bomback et al. [38] recently
askedsomewhat tongue in cheekRenal aspirinwill
all patients with chronic kidney disease one day take
spironolactone?suggesting that much of the extrarenal
pathology in uraemic patients is caused by the ugly effects
[19] of high aldosterone in a high-salt environment.
Aldosterone is not only of interest in end-stage kid-
ney disease but also plays a role in the progression of
chronic kidney disease. An adverse effect of aldosterone
on the kidney is suggested by the observation that at com-
parable levels of blood pressures, patients with primary
aldosteronism have more pronounced proteinuria than
patients with essential hypertension [39]. In patients with
primary kidney disease, Ruggenenti et al. as well as Walker
found a correlation between aldosterone concentrations
and deterioration of renal function. [40,41]. Plasma aldos-
terone concentrations are elevated early on when GFR is
70 ml/min [42]. These findings raised the obvious ques-
tion whether spironolactoneindependent of blockade of
the reninangiotensin systemwould be another agent
suitable to limit renal injury. In patients with proteinuria
>1 g/24 h, despite ACE inhibitor treatment, Chrysostomou
and Becker [43] added 25 mg spironolactone to the regi-
men and observed an average reduction of proteinuria by
54% without significant change in blood pressure or crea-
tinine concentration. This observation has been confirmed
by others, particularly in patients with type 2 diabetes [44].
Therapy-resistant hypertensionthe role of
mineralocorticoid receptor blockade
Many major hypertension intervention trials came to the
conclusion that a large proportion of patients fail to achieve
the goal blood pressure proposed by the Joint National
Committee VII [45]. Progressively higher proteinuria is
found in patients with resistant hypertension at progres-
sively higher tertiles of salt intake and this is paralleled by
progressively higher urinary aldosterone excretion [46]. In a
cohort of patients with resistant hypertension, plasma aldos-
terone/renin ratios and urinary aldosterone excretion rates
were higher than in controls and this was associated with
biomarkers (ANP, BNP) pointing to hypervolaemia [47]
In resistant hypertension defined by the Joint National
Committee VII [48] as failure to achieve goal BP when
a patient adheres to maximum-tolerated doses of three an-
tihypertensive drugs, including a diuretic, the addition of
spironolactone as the fourth line treatment is highly effec-
tive as recently again illustrated by the ASCOT trial [49].
Proteinuria escapethe role of aldosterone and
consequences for treatment of renal patients
with proteinuria
In proteinuric patients treated with ACEinhibitors or ARBs,
protein excretion usually decreases, but after 13 years a
secondary increase of proteinuria (escape) is observed
in a large proportion of patients. Such escape is paral-
leled by an increase in the initially lowered plasma aldos-
terone concentration [50] and is associated with more rapid
loss of GFR as documented in several studies on diabetic
nephropathy [51]. The recently unpublished paediatric ES-
CAPE study showed that despite excellent blood pressure
control, 50% of patients on intensified blood pressure con-
trol and RAS blockade were back again after approximately
3 years at baseline protein excretion.
Intervention studies indicate that prevention of aldos-
terone escape is possible to some extent by intensifying
RAS blockade as also shown in patients with congestive
heart failure [52]. In diabetic nephropathy, following the
communication of Sato et al. [53], reversal of proteinuria
escape by adding spironolactone has been confirmed by
numerous investigators. Experimental studies showed that
aldosterone and eplerenone restored reduced expression of
podocine by podocytes [17]. In patients with nephrotic pro-
teinuria on ACE inhibitors plus ARBs, addition of spirono-
lactone (but not addition of thiazides) caused a further de-
crease of proteinuria unrelated to blood pressure [54]. Un-
fortunately, this strategy is associated with a substantial risk
of hyperkalaemia, first described by Schepkens et al. [55],
which necessitates careful instruction and supervision of
such patients.
Conflict of interest statement. None declared.
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Received for publication: 23.3.09; Accepted in revised form: 15.4.09