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Nephrol Dial Transplant (2009) 1 of 4doi: 10.1093/ndt/gfp206

Editorial Comment

Aldosterone, a vasculotoxic agentnovel functions for

an old hormone

Eberhard Ritz 1 and Andreas Tomaschitz 2

1Department of Internal Medicine, Klinikum der Universit at Heidelberg, Nierenzentrum, Im Neuenheimer Feld 162, 69120Heidelberg, 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 Connsyndrome

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 Framinghamoffspring study, it had been documented that the frequencyof a rise in blood pressure and the incidence of hyper-tension increase progressively from the first to the fourthquartile of serum aldosterone concentrations [3]. This led recently to the comment whether primary aldosteronismis as widespread as some believe may not be as relevantas whether the commonly prevailing level of aldosteroneis too high for the amount of sodium we consume [4]. Inline with the idea that aldosterone plays a more generalrole 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]. Thisinterpretation finds support in some recent experimentaldata. Makhanova [5] created salt-sensitive blood pressurein mice by increasing the expression of aldosterone syn-thase by manipulating the untranslated regions of aldos-terone synthase gene in mice, raising aldosterone synthasemRNA 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 byhypokalaemiaand increasedex- pression of collecting duct sodium channel (ENaC). Alongthese lines, a study in humans [6] found a correlation be-tween an aldosteronesynthase polymorphism (344T/C) and aldosterone excretion as well as hypertension; this obser-vation has recently been confirmed by one study [7] butnot 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 by11mmHg, remarkably without a change in serum potassiumand presumably as a result of a direct vascular effect [9].

Activation of the mineralocorticoid

receptorbeyond aldosteroneWhen I.S. Edelman characterized the mineralocorticoid receptor, he had difficulties to publish the f inding be-cause the receptor was orders of magnitudes more sen-sitive to cortisol than to aldosterone. This paradox hassubsequently 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 conversionis catalyzed by 11-beta-hydroxysteroid dehydrogenase-2(11-beta-HSD-2), malfunction of which is associated withseveral 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 from the sea to land life when morestringent conservation of sodium was required.

More relevant for the recent epidemic of hypertensionassociated with high aldosterone concentrations is the ob-servation that visceral obesity is associated with elevated al-dosterone [11], mainly because human visceral adipocytessecrete 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

C The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please e-mail: journals.permissions@oxfordjournals.org

NDT Advance Access published May 27, 2009

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significantly correlated with the risk of onset of themetabolic syndrome [14]. In an animal model of themetabolic syndrome, aldosterone caused podocyte in- jury [15] with proteinuria responsive to treatment witheplerenone [16] and tempol [17] pointing to a role of oxyda-tive stress.

Aldosterone actionsbeyond the classicalmineralocorticoid receptor

The classical concept of aldosterone was that aldosteronesynthesized in the adrenal cortex acted in an endocrinefashion 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 theinteraction 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 aldosteroneon transport epithelia, non-classical effects on interstitialtissues, specifically endothelial cells, fibrocytes, have morerecently 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-sium homeostasis, thus avoiding hypotension in land-livingspecies.

The bad : in the presence of high-salt intake, aldosteronecauses 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 damagecaused via inflammatory or pro-fibroticpathways involvingoxydative stress, activation of NF-kappa-B, AP-1, NADP-oxydase, ICAM, VCAM and others.

Aldosteroneblood pressure-independent target

organ damageA most elegant experiment in human endothelial cell mono-layer cultures was reported by Oberleithner [20]: when theextracellular sodium concentration was increased above athreshold 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 wasmediated 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 neighbouringvascular smooth muscle cells function causing increased vascularstiffness and resistance[21].A correlation betweenindices of vascular stiffness and aldosterone-to-renin ratioswas 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 drugsreduced blood pressure, only spironolactone but not thethiazide reduced the pulse wave velocity; this effect was blood pressure independent, pointing to direct endothe-lial cell and vascular actions of aldosterone. Such directeffects 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 wasdocumented in the heart of patients with cardiac failure[26].

Such blood pressure-independent and natriuresis-

independent effects explain the benefit observed withthe effect of non-natriuretic doses of spironolactone or eplerenone in patients with severe heart failure, i.e. in theRALES [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 malignantnephrosclerosis [31], manoeuvressuch 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 increasein plasma aldosterone [33] of the adrenal gland, whileconversely 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 causesevenregression 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, thePima Indians, who live on minimal sodium intake (natriure-sis 1 1.5 mmol/day): they have low blood pressure values(102/62 mmHg) despite serum aldosterone concentrationsabove the usual concentration in Conn syndrome (85.6 78 ng/dl [36]. In animal experiments, high-salt environmentis found to be associated with an inflammatory response(NF-kappa-B), diminished nitric oxide release as well asinflammatory infiltrates and tissue remodelling [37].

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Against this background, Bomback et al. [38] recentlyaskedsomewhat tongue in cheekRenal aspirinwillall patients with chronic kidney disease one day takespironolactone?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 aldosteroneon the kidney is suggested by the observation that at com- parable levels of blood pressures, patients with primaryaldosteronism 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 concentrationsand deterioration of renal function. [40,41]. Plasma aldos-terone concentrations are elevated early on when GFR is

70 ml/min [42]. These f indings raised the obvious ques-tion whether spironolactoneindependent of blockade of the reninangiotensin systemwould be another agentsuitable 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 by54% without significant change in blood pressure or crea-tinine concentration. This observation has been confirmed by others, part icularly in patients with type 2 diabetes [44].

Therapy-resistant hypertensionthe role of mineralocorticoid receptor blockade

Many major hypertension intervention trials came to theconclusion that a large proportion of patients fail to achievethe goal blood pressure proposed by the Joint NationalCommittee VII [45]. Progressively higher proteinuria isfound 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 acohort of patients with resistant hypertension, plasma aldos-terone/renin ratios and urinary aldosterone excretion rateswere higher than in controls and this was associated with biomarkers (ANP, BNP) pointing to hypervolaemia [47]

In resistant hypertension defined by the Joint NationalCommittee VII [48] as failure to achieve goal BP whena 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 andconsequences for treatment of renal patientswith proteinuria

In proteinuric patients treatedwith ACE inhibitorsor ARBs, protein excretion usually decreases, but after 13 years asecondary 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 diabeticnephropathy [51]. The recently unpublished paediatric ES-CAPE study showed that despite excellent blood pressurecontrol, 50% of patients on intensified blood pressure con-trol and RAS blockade were back again after approximately3 years at baseline protein excretion.

Intervention studies indicate that prevention of aldos-

terone escape is possible to some extent by intensifyingRAS blockade as also shown in patients with congestiveheart failure [52]. In diabetic nephropathy, following thecommunication of Sato et al. [53], reversal of proteinuriaescape by adding spironolactone has been confirmed bynumerous investigators. Experimental studies showed thataldosterone 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