Review

Continuing Medical EducationNature Clinical Practice Nephrology (2007) 3, 486-492
doi:10.1038/ncpneph0575  
Received 29 March 2007 | Accepted 13 June 2007

The incidence and implications of aldosterone breakthrough

Andrew S Bomback* and Philip J Klemmer  About the authors

Correspondence *University of North Carolina Kidney Center, 7024 Burnett-Womack Building, Campus Box 7155, Chapel Hill, NC 27599–7155, USA

Email abomback@unch.unc.edu

Summary

Interruption of the renin–angiotensin–aldosterone system has become a leading therapeutic strategy in the treatment of chronic heart and kidney disease. Angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers do not, however, uniformly suppress the renin–angiotensin–aldosterone system. Plasma aldosterone levels are elevated in a subset of patients despite therapy. This phenomenon, known as 'aldosterone escape' or 'aldosterone breakthrough', has only been directly examined in small numbers of patients. The key questions of how often breakthrough occurs and whether breakthrough leads to worse outcomes have yet to be definitively answered. In this Review, we summarize the reported data on the incidence and clinical implications of aldosterone breakthrough, and highlight areas of uncertainty that have yet to be adequately addressed in the literature. Although the available evidence is not strong enough to support widespread screening for aldosterone breakthrough, our findings should prompt physicians to consider the phenomenon in select patients as well as guide future research efforts.

Review criteria

We searched MEDLINE (1960 to January 2007) using the search terms "aldosterone escape" and "aldosterone breakthrough." We also searched the bibliographies of identified publications, including previous narrative reviews and editorials. Studies that met the following criteria were considered for inclusion: subjects were adult patients on chronic (>4 weeks) ACE inhibitor and/or ARB therapy, investigators used a prespecified definition of aldosterone breakthrough, and breakthrough outcomes were reported as an incidence proportion over the study period. We excluded studies that used only sample mean values for aldosterone before and after therapy, as mean values might mask individual changes in aldosterone levels and result in misclassification of breakthrough. We focused on describing studies and results qualitatively rather than quantitatively because of marked variation in study designs, participants, interventions and reported outcome measures.

Keywords:

aldosterone breakthrough, aldosterone escape, angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, chronic kidney disease

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Learning objectives

Upon completion of this activity, participants should be able to:

  1. Define aldosterone breakthrough in the context of angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) use.
  2. Describe the incidence of aldosterone breakthrough among patients on ACE inhibitors and ARBs.
  3. List risk factors for aldosterone breakthrough in patients on ACE inhibitors or ARBs.
  4. Describe clinical outcomes associated with aldosterone breakthrough.
  5. Identify a rationale and the method for screening patients for aldosterone breakthrough.

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Introduction

Interruption of the renin–angiotensin–aldosterone system (RAAS) with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), alone or in combination, has become a leading therapeutic strategy to slow the progression of chronic heart and kidney disease. This is an effective, but not perfect, approach; a considerable proportion of patients progress despite this therapy.

In clinical trials of ACE inhibitors and ARBs, plasma aldosterone levels, after an initial decline, have been shown to increase in some patients over the long-term.1, 2, 3, 4, 5, 6 This phenomenon, termed 'aldosterone escape' or 'aldosterone breakthrough' (in this Review, we use the term 'aldosterone breakthrough' to avoid confusion with 'aldosterone escape' from the sodium-retaining action of mineralocorticoids, an unrelated clinical entity), could have important clinical consequences given aldosterone's nonepithelial, profibrotic actions on diverse organ systems, including the heart and kidney.7, 8, 9, 10

Aldosterone breakthrough, however, has only been examined directly in small patient samples drawn from heterogeneous populations. At present, there is no clear consensus on such key questions as how often breakthrough occurs and whether breakthrough has clinical significance. We, therefore, systematically reviewed the literature to determine the incidence and clinical implications of aldosterone breakthrough among patients receiving long-term ACE inhibitor and/or ARB therapy.

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Aldosterone and fibrosis

Aldosterone-mediated activation of mineralocorticoid receptors in nonepithelial tissues, in the presence of high extracellular sodium (sodium cofactor), promotes tissue inflammation and injury in the cardiovascular and renal systems. In animal models, administration of aldosterone with excess salt produces cardiac fibrosis and hypertrophy, independent of blood pressure, reflecting a direct effect of aldosterone on the heart.11, 12 Similarly, unopposed aldosterone exacerbates glomerulosclerosis and causes severe proteinuria via nonepithelial, profibrotic effects on the kidney.13, 14, 15 Aldosterone's nonepithelial effects might, therefore, have a more important role in the pathogenesis of chronic heart and kidney disease than its classical, epithelial effects.16

These profibrotic effects, the potential sequelae of aldosterone breakthrough, could explain why mortality of patients with congestive heart failure (CHF), who are routinely treated with agents that block the RAAS, is reduced when mineralocorticoid receptor blockers (MRBs) are added to traditional heart failure regimens.17, 18 Similarly, aldosterone breakthrough might account for recent studies in which MRBs markedly ameliorated proteinuria in patients with chronic kidney disease (CKD) who were already receiving high doses of ACE inhibitors and/or ARBs.19, 20, 21, 22 ACE inhibitors and/or ARBs are the most widely used treatments for CHF and CKD; if aldosterone breakthrough occurs in a significant subset of treated patients, then disease progression might occur in spite of standard-of-care therapy.

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Incidence of aldosterone breakthrough

Our literature search (see 'Review Criteria' section) detected 190 studies. Review of titles and abstracts showed that 16 studies initially met the inclusion criteria (Figure 1). Review of the full articles led to exclusion of a further six studies that reported only sample mean values of aldosterone before and after treatment with ACE inhibitors and/or ARBs without measuring cumulative incidence of the phenomenon,1, 2, 3, 23, 24, 25 and two studies whose subjects were included in other, larger studies.5, 26 Of the eight studies included in this Review, four enrolled subjects with CHF,6, 27, 28, 29 three enrolled subjects with CKD,4, 30, 31 and one enrolled hypertensive subjects without known cardiac or renal disease.32 Sample sizes ranged from 22 to 141 subjects.

Figure 1 Process by which studies were selected for inclusion in this Review
Figure 1 : Process by which studies were selected for inclusion in this Review Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker.

Full figure and legend (31K)Figures & Tables indexDownload PowerPoint slide (146K)

Depending on the definition used for aldosterone breakthrough, the incidence of the phenomenon ranged from 10% over 6 months to 53% over 1 year (Table 1). The risk of aldosterone breakthrough differed according to the investigators' predetermined definition. In studies that defined breakthrough as any increase from an individual's baseline serum aldosterone level (i.e. before ACE inhibitor and/or ARB therapy), the incidence ranged from 40% over 10 months to 53% over 12 months. Studies that used absolute cutoff values of serum aldosterone—determined from samples of healthy control subjects—detected lower risks of breakthrough, with cumulative incidences ranging from 10% over 6 months to 38% over 1 month.

Table 1 Overview of studies reviewed during preparation of this article
Table 1 - Overview of studies reviewed during preparation of this article
Full tableFigures & Tables indexDownload PowerPoint slide (192K)

The risk of aldosterone breakthrough also seemed to differ according to comorbidity status; the incidence of breakthrough was lower in patients with CHF than in patients without CHF. The studies that enrolled patients with CHF used absolute cutoff values of serum aldosterone as their definitions of breakthrough; therefore, the apparent association between comorbidity status and breakthrough is probably a reflection of the aforementioned differences in prespecified definitions of breakthrough.

Three studies directly addressed whether the incidence of aldosterone breakthrough was related to the dose or class of RAAS blockade. MacFadyen et al. enrolled subjects who were taking a variety of ACE inhibitors, normalized treatment to a bioequivalent daily dose of enalapril, and found no association between dose of ACE inhibitor and incidence of breakthrough.6 Similarly, Tang et al. found no significant difference in the incidence of breakthrough between groups of patients randomly assigned to low-dose or high-dose enalapril.29 Horita et al. found equal rates of breakthrough among subjects on ACE inhibitors, ARBs, or a combination of both.31

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Implications of aldosterone breakthrough

Of the eight studies included in our Review, five reported on clinical outcomes associated with aldosterone breakthrough. Sato and Saruta followed 75 essential hypertensive patients on ACE inhibitors for 40 weeks. Although subjects both with and without breakthrough experienced similar blood pressure reductions during ACE inhibitor therapy, only patients without breakthrough experienced concomitant decreases in left ventricular mass index. This marker of left ventricular hypertrophy did not change among patients who experienced aldosterone breakthrough.32

Cicoira et al. followed 141 patients with CHF on chronic ACE inhibitor therapy to determine whether aldosterone breakthrough was related to disease severity or functional impairment. Echocardiography showed that left ventricular volume, ejection fraction, left atrial volume, and mitral flow Doppler parameters were independent of breakthrough status. By contrast, exercise capacity, mean peak oxygen consumption and the slope of the relationship between ventilation and carbon dioxide production (a measure of the ventilatory response during exercise) were markedly worse in patients who had experienced breakthrough than in those who had not.28

Three studies examined aldosterone breakthrough in CKD populations and found important clinical correlations. Sato et al. followed patients with diabetic nephropathy and, after 40 weeks of ACE inhibitor therapy titrated upward to a goal blood pressure of 130/85 mmHg, the researchers found markedly higher urinary albumin excretion rates among those who experienced aldosterone breakthrough than among those who did not.30 In their study of patients with IgA nephropathy, Horita et al. also found urinary protein excretion rates to be higher in patients who experienced aldosterone breakthrough.31 By contrast, Schjoedt et al. found no difference in albuminuria between breakthrough and non-breakthrough patients with diabetic nephropathy. These investigators did, however, detect a considerably faster decline in glomerular filtration rate in patients who experienced aldosterone breakthrough (median 5.0 ml/min/year) than in those who did not (median 2.4 ml/min/year).4

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Mechanism of aldosterone breakthrough

Plasma aldosterone levels are chiefly regulated by potassium and by angiotensin II in response to salt balance and plasma volume. Alterations in aldosterone levels might, therefore, reflect alterations in plasma potassium concentration, total extracellular sodium, and effective blood volume in the systemic arterial circulation. Precise measurement of the incidence of aldosterone breakthrough should account for these factors before and after RAAS-blocking therapy. Only Schjoedt et al. reported both baseline and end point values for potassium and angiotensin II stratified by breakthrough status.4 Although these investigators found pretreatment and post-treatment potassium levels to be identical among subjects with and without breakthrough, and pretreatment angiotensin II levels to be nearly matched, the breakthrough patients did have, on average, higher post-treatment angiotensin II levels (35 pmol/l versus 23 pmol/l).

The most favored explanation for aldosterone breakthrough is that non-ACE enzymes are capable of cleaving angiotensin I to angiotensin II, and aldosterone breakthrough is then simply the result of angiotensin II breakthrough.33, 34 If aldosterone breakthrough is, in fact, mediated through angiotensin II levels, this might explain the greater tendency towards breakthrough in patients with declining kidney and heart function; in such cases, the rise in aldosterone levels would be a consequence, and not a cause, of target organ injury. A mechanism for aldosterone breakthrough mediated by angiotensin II would, however, indicate that the phenomenon occurs less often in patients on ARBs than in those receiving ACE inhibitors, which has not been the case.

The increase in plasma potassium levels during ACE inhibitor and/or ARB therapy has also been advanced as an explanation for aldosterone breakthrough. The available evidence does not support this hypothesis. In addition to the results of Schjoedt et al., Sato and Saruta reported that potassium levels did not change during 40 weeks of ACE inhibitor therapy, regardless of breakthrough status.32 Two other studies detected similar end point (i.e. post-RAAS blockade) potassium concentrations among subjects with and without aldosterone breakthrough.28, 30

Factors other than potassium and angiotensin II have demonstrated ability to either stimulate (e.g. corticotrophin, prolactin, serotonin, vasopressin) or inhibit (e.g. atrial natriuretic hormone, nitric oxide, somatostatin) aldosterone production. Among these factors, however, in vivo physiological significance has been demonstrated for corticotrophin (adrenocorticotropic hormone) and atrial natriuretic hormone only.35 Blockade of the RAAS should not appreciably affect either of these parameters. As such, their role in aldosterone breakthrough is likely to be negligible, although no study of breakthrough to date has directly addressed these factors.

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Areas of uncertainty

Screening for aldosterone breakthrough

We believe that the optimum definition for aldosterone breakthrough is a serum aldosterone level that exceeds a baseline (pre-ACE inhibitor and/or ARB therapy) value 6–12 months after initiation of RAAS-blocking therapy. This definition is the most conservative as well as the most clinically relevant, given the desire to block the RAAS with escalating doses of ACE inhibitors and ARBs. Using standardized cutoff values on the basis of population averages or levels in healthy controls would probably underestimate the incidence of breakthrough. If possible, serum aldosterone concentrations should be interpreted in reference to sodium cofactor, but we acknowledge that accurate measurement of dietary sodium intake and/or urinary sodium excretion are usually not practical in clinical settings.

The next issue, which logically arises from our preferred definition of aldosterone breakthrough, is whether all patients receiving ACE inhibitors and/or ARBs should be screened for breakthrough. Our definition requires physicians to check aldosterone levels before prescribing ACE inhibitors and/or ARBs and, again, 6–12 months later. This is obviously not the current standard of care, although most patients on these drugs do have other laboratory values checked at least once or twice a year. Assuming that aldosterone breakthrough screening would involve two additional blood tests per year, is such a surveillance program cost-beneficial? Only prospective, sufficiently-powered clinical trials that identify breakthrough and clinical outcomes associated with breakthrough will be able to answer this question definitively. Our Review does not provide sufficient evidence to support widespread screening, but it should prompt physicians whose patients demonstrate refractory hypertension, worsening ejection fraction, persistent proteinuria or declining glomerular filtration rate despite ACE inhibitors and/or ARBs to check for aldosterone breakthrough.

Aldosterone breakthrough and renin inhibition

Renin inhibitors suppress the RAAS in its earliest stage without accumulation of active precursor substances. This new class of anti-hypertensive medication might, therefore, be associated with less aldosterone breakthrough than conventional RAAS blockade with ACE inhibitors and/or ARBs.36, 37 In a study of 18 healthy volunteers given the renin inhibitor aliskerin, Nussberger et al. reported dose-dependent decreases in plasma angiotensin II concentrations and plasma and urinary aldosterone concentrations.38 Subjects were only followed for 8 days, however, and in this early crossover trial, similar neurohormonal reductions were seen when subjects took a 20 mg dose of enalapril for 8 days. Azizi et al. administered single doses of aliskerin, valsartan, a combination of both drugs, or placebo to 12 mildly sodium-depleted normotensive individuals.39 Plasma angiotensin II levels decreased only after renin inhibition alone; plasma aldosterone concentrations decreased significantly, but to equal degrees, with all three active treatments. Neither of these studies compared long-term use of renin inhibitors with traditional RAAS-blocking drugs.

Aldosterone antagonism for aldosterone breakthrough

We believe that an important, and heretofore unanswered, question is whether augmentation therapy with MRBs should be aimed primarily at patients with aldosterone breakthrough. If breakthrough is considered a 'refractory hyperaldosteronism',40 then aldosterone antagonism should constitute effective therapy. The landmark CHF trials of MRBs—RALES and EPHESUS—did not result in publication of subgroup analyses on the basis of aldosterone levels. The RALES Neurohormonal Substudy, reporting in abstract form on 125 of the trial's 1,663 subjects, showed that the mortality benefits of spironolactone in CHF were independent of baseline aldosterone levels.41 This finding could be due, in part, to occupation of mineralocorticoid receptors by glucocorticoids, in which case aldosterone alone cannot fully account for activation of the mineralocorticoid receptor or the demonstrated cardiovascular benefits of blocking this receptor.42, 43 Furthermore, aldosterone breakthrough is not the only counter-regulatory stimulus to the RAAS in patients with CHF or CKD. Elevated potassium levels, use of diuretics, decompensated heart failure, and declines in blood pressure can also stimulate the RAAS, potentially prompting a need for higher levels of blockade with MRBs.

MRBs, however, are associated with a considerable risk of hyperkalemia in everyday practice,44 particularly in patients with chronic heart and kidney disease who rely on aldosterone to remain in potassium balance. As with any medical intervention, MRB therapy should be targeted towards those patients who would receive the greatest benefit with the least risk of adverse events. If future studies confirm that aldosterone breakthrough, a physiological stimulus that lowers levels of body potassium, imparts a high risk for morbidity and mortality in the CHF and CKD populations, then patients with breakthrough might turn out to be prime candidates for MRB therapy; that is, the patients who would receive the greatest benefit from the intervention with the least risk of hyperkalemia.

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Conclusions

This Review has summarized the reported incidence and clinical implications of aldosterone breakthrough, as well as highlighted the gaps in our understanding of the phenomenon. The eight studies discussed indicate that aldosterone breakthrough occurs in a significant proportion of patients on long-term ACE inhibitor and/or ARB therapy, and that the phenomenon might be associated with important cardiovascular and renal outcomes, including left ventricular hypertrophy, poor exercise tolerance, refractory proteinuria, and declining glomerular filtration rate. These results, drawn from small studies with heterogeneous patient populations and methodological limitations, should be considered to be hypothesis-generating and fuel further, more-rigorous research.

At present, there is insufficient evidence to advocate screening for aldosterone breakthrough in all asymptomatic patients receiving ACE inhibitors and/or ARBs. We feel, however, that the data are strong enough for clinicians to consider—and to test for—the phenomenon in patients with refractory heart and kidney disease despite maximal RAAS-blocking therapy. If breakthrough is detected in the setting of stable potassium and salt balance, then the addition of aldosterone antagonists or renin inhibitors to conventional heart and kidney failure regimens could improve clinical outcomes.

Key points

  • Serum aldosterone levels are increased in a subset of patients treated with angiotensin-converting-enzyme inhibitors and/or angiotensin-receptor blockers, a phenomenon known as 'aldosterone breakthrough'
  • A small number of studies indicate that the incidence of aldosterone breakthrough is between 10% and 53%
  • The wide range in the reported incidence of breakthrough is probably attributable to the use of different definitions, and to comorbidity status
  • Aldosterone breakthrough could be associated with left ventricular hypertrophy, decreased exercise capacity, and higher rates of urinary albumin excretion
  • Clinicians should consider testing for aldosterone breakthrough in patients with refractory heart or kidney disease despite maximal therapeutic blockade of the renin–angiotensin–aldosterone system
  • Breakthrough detected in the setting of stable potassium and salt balance could warrant the addition of aldosterone antagonists or renin inhibitors to conventional heart and kidney failure regimens

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Acknowledgments

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Competing interests

The authors declared no competing interests.

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