Background

The renin-angiotensin-aldosterone system (RAAS) contributes to hypertension and nephropathy. Until recently, aldosterone either has not been considered or has been considered a relatively minor component of the process—a contribution that could be negated with angiotensin-converting enzyme (ACE) inhibition or angiotensin receptor blockade.

Methods

A Medline search was performed to identify relevant literature describing the role of aldosterone in the pathogenesis of renal dysfunction.

Results

Growing evidence from experimental and clinical studies indicates that increased aldosterone is an independent contributor to small- and medium-sized arterial injury and nephropathy. Excess mineralocorticoid receptor stimulation of local and systemic origin promotes target organ dysfunction, vascular injury, and fibrosis, independent of the effects of other elements of the RAAS. Blockade of the RAAS with ACE inhibition or angiotensin receptor blockade often does not confer optimal protection from the effects of mineralocorticoids on small- and medium-sized blood vessels. Recent preliminary data from clinical studies indicate that aldosterone blockade protects the kidneys, sharply decreases proteinuria, beyond the activities of ACE inhibition or angiotensin receptor blockade and independent of beneficial blood pressure effects, and can protect patients from vascular injury associated with diabetes mellitus and hypertension.

Conclusion

Aldosterone blockade with the selective aldosterone blocker eplerenone, in combination with other RAAS inhibitors, is probably renoprotective and should be considered as a component of the treatment regimens of diabetic and hypertensive patients at risk for renal or cardiovascular disease expression. A high priority should be placed on developing the randomized, controlled trials required to establish that role.

ANGIOTENSIN II AND ALDOSTERONE IN BLOOD PRESSURE CONTROL

Angiotensin II

Angiotensin II (Ang II) is an octapeptide generated by the action of ACE on the inactive precursor angiotensin I. Ang II produces systemic vasoconstriction by binding to type 1 angiotensin (AT1) receptors throughout the body. In the kidney, this action appears to be, at least in part, mediated through protein kinase C (PKC) activation⁷. The process may be facilitated by an Ang II-induced enhancement of noradrenergic neurotransmission⁸. In addition, Ang II promotes salt and water retention through two mechanisms: (1) direct stimulation of sodium resorption in the proximal convoluted tubule through endocrine, paracrine, and autocrine processes; and (2) stimulation of aldosterone secretion^9,10.

Aldosterone

Cells of the zona glomerulosa layer of the adrenal cortex synthesize aldosterone. Although deoxycorticosterone, corticosterone, and cortisol all have mineralocorticoid properties, aldosterone is the principal mineralocorticoid produced by the adrenal gland. A crucial recent advance involves recognition that endothelial and vascular smooth muscle cells (VSMCs) in the heart, blood vessels, and brain also can synthesize aldosterone^11,12,13. Acting through epithelial mineralocorticoid receptors in the kidney, sweat glands, and colon and, to a lesser extent, nonepithelial mineralocorticoid receptors in the brain and cardiovascular system, aldosterone plays a major role in salt and water homeostasis and potassium excretion^14,15,16. More recently, it has become apparent that aldosterone also modulates the growth of fibroblasts or myofibroblasts and, in association with transforming growth factor (TGF-), helps regulate collagen deposition in the heart and blood vessels^17,18,19.

RAAS inhibition and renal injury

Injury to the kidney mediated by the renin-angiotensin-aldosterone system (RAAS) could occur through multiple mechanisms. Impaired renal autoregulation could allow changes in systemic blood pressure to be transmitted into the glomerulus and the peritubular capillaries²⁰. This increased intraglomerular pressure could produce injury with both glomerulosclerosis and tubulointerstitial damage²¹. RAAS-mediated injury also could develop through ischemia secondary to hypertension-induced arteriolar sclerosis. Both preclinical and clinical evidence indicate that interruption of the RAAS ameliorates renal vascular remodeling and associated injury in patients with hypertension.

The role of the RAAS in the development of renal injury has been demonstrated repeatedly in preclinical studies^22,23,24,25. In stroke-prone spontaneously hypertensive rats and other experimental models, ACE inhibitors have been shown to block Ang II formation in the renal vasculature, reduce arterial vasoconstriction, and decrease glomerular capillary pressure^22,23,24,25. The effect is at least partially independent of the blood-pressure lowering effects of these drugs.

The renoprotective effects of RAAS inhibition have been confirmed unambiguously in humans. Randomized, clinical trials of RAAS blockade in patients with renal disease (with or without diabetes) indicate that ACE inhibitors and ARBs provide renal protection independent of their effects on systemic blood pressure^{26,27,28,29,30,31,32,33}. In an analysis of 11 randomized controlled trials in patients with nondiabetic renal disease, ACE inhibitors produced a 31% decrease in the relative risk of developing end-stage renal disease (ESRD) compared to regimens that did not include ACE inhibitors³⁴. Blockade of the RAAS through the use of ARBs also has been shown to be renoprotective in patients with type 2 diabetes. Results from the Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENNAL) study, Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA) study, and Irbesartan Diabetic Nephropathy Trial (IDNT) demonstrated that ARBs reduce the progression of renal disease^31,32,33. The renoprotection produced by ARBs was similar to that of ACE inhibitors, suggesting that a common mechanism is involved, but head-to-head trials are needed to confirm this hypothesis.

ALDOSTERONE AND RAAS-INDUCED VASCULAR INJURY AND NEPHROPATHY

Preclinical evidence strongly indicates that aldosterone, per se, is an essential link between hypertension and the development of vascular remodeling and hypertensive nephropathy. Clinical evidence is preliminary but is strongly supportive.

Aldosterone in the remnant kidney model

Greene, Kren, and Hostetter¹ evaluated the independent role of aldosterone in renal injury in the remnant kidney model and focused on the response of aldosterone to RAAS inhibition. In the initial stage of the experiment, rats were divided into four groups: (1) sham-operated rats, (2) untreated remnant kidney rats (REM), (3) REM rats treated with losartan and enalapril (REM Ang II antagonists), and (4) REM Ang II antagonist rats infused with exogenous aldosterone (REM Ang II antagonist + aldo). Aldosterone was infused continuously in the last group to maintain aldosterone levels comparable with those in untreated REM rats. Activation of the aldosterone component of the RAAS in REM rats was indicated by their larger adrenal glands plus >tenfold elevation in plasma aldosterone compared with animals in the sham group. Rats with remnant kidneys treated with an ARB and an ACE inhibitor demonstrated significant suppression of hyperaldosteronism plus significant attenuation of proteinuria, hypertension, and glomerulosclerosis compared with untreated REM animals. Infusion of aldosterone into REM Ang II antagonist animals increased proteinuria, hypertension, and glomerulosclerosis compared with REM Ang II antagonist rats that did not receive exogenous aldosterone. The importance of aldosterone in this model is reflected in the reversal of the protective effects of treatment with losartan and enalapril; after 4 weeks, the physiologic and morphologic changes in the REM Ang II antagonist group that also received exogenous aldosterone were identical to the changes in untreated REM animals.

Approaching the issue from a different perspective, Quan, Walser, and Hill³⁵ evaluated the independent effects of aldosterone and dietary protein intake. Partially nephrectomized rats underwent adrenalectomy followed by either low- or high-dose corticosterone replacement therapy. All animals were provided a choice of water or saline to drink. Proteinuria was significantly increased by the presence of intact adrenal glands, higher corticosterone maintenance level, and higher dietary protein. Because the animals had access to both salt and water ad libitum, the extracellular fluid volume was identical in the groups. Both adrenalectomy and protein restriction improved renal histopathology scores. The final glomerular filtration rate (GFR) was significantly improved by adrenalectomy when nonsurvivors were scored as having zero clearance, but not if the analysis was limited to survivors. The GFR was not affected by diet or by corticosterone level. The investigators concluded that removal of the source of endogenous mineralocorticoids with adrenalectomy could ameliorate the effects of renal ablation, whereas corticosterone replacement only altered the degree of proteinuria.

Aldosterone in spontaneously hypertensive rats

Horiuchi et al³⁶ investigated the role of aldosterone in the stroke-prone spontaneously hypertensive rat model by comparing the characteristics of the strain's cytosolic mineralocorticoid receptors with those of normotensive Wistar-Kyoto rats. By 6 weeks of age, the animals were hypertensive, exhibited an increased concentration of renal cytosolic aldosterone receptors, and showed decreases in urine sodium and volume. Plasma aldosterone levels, however, were similar to those of the normotensive Wista-Kyoto rats. By 10 weeks of age, plasma aldosterone concentrations became significantly higher than those in the Wistar-Kyoto animals. Notably, although the concentration of the mineralocorticoid receptor was elevated in the stroke-prone spontaneously hypertensive animals, the receptors' molecular properties did not differ from those of the controls. These data suggest that an elevated concentration of aldosterone receptors in these animals may be a significant factor in their predisposition to hypertension and its associated vascular injury.

To evaluate the role of mineralocorticoid receptor blockade in the progression of vascular injury in saline-drinking stroke-prone spontaneously hypertensive rats, Rocha et al³⁷ implanted time-release pellets containing 200 mg of spironolactone. Spironolactone treatment significantly decreased proteinuria (P < 0.0001). The blockade of mineralocorticoid receptors also significantly increased survival. Although both the control and the spironolactone-treated populations were severely hypertensive, all but one of the control rats had evidence of stroke and died by 16 weeks of age; conversely, the spironolactone-treated animals remained asymptomatic through 19 weeks (P < 0.03). In addition urinary protein excretion did not increase from baseline levels during spironolactone treatment, whereas urinary protein levels were significantly elevated in controls (P < 0.0001) Figure 1. Microscopic examination demonstrated that spironolactone protected the animals from the development of malignant nephrosclerotic and cerebrovascular lesions. Compared with controls, mineralocorticoid receptor blockade produced no differences in systolic blood pressure or excretion of water or electrolytes.

Figure 1.

Effect of spironolactone on urinary protein excretion in stroke-prone spontaneously hypertensive rats. Line graphs showing (A) systolic arterial blood pressure (SBP) and (B) urinary protein excretion (UPE) in stroke-prone spontaneously hypertensive rats into which time-release pellets containing spironolactone or placebo were implanted. Values are mean SEM. Numbers in parenthesis indicate the number of animals. *P < 0.001 compared with placebo-implanted controls. Reprinted with permission from Rocha et al³⁸.

Full figure and legend (20K)

To evaluate the role of the various elements of the RAAS, the development of hypertension-associated vascular lesions was further evaluated in this model. Rocha et al³⁸ studied the effects of chronic aldosterone infusion on vascular lesions in animals treated with captopril. Animals were divided into four groups: (1) vehicle alone, (2) captopril alone, (3) aldosterone alone, and (4) combined dosing with captopril plus aldosterone at two different dose levels. All animals had significantly elevated blood pressure. Animals treated with either vehicle or aldosterone alone developed severe proteinuria and had arteriolar and glomerular thrombotic and proliferative lesions Figure 2. Animals treated with captopril alone had reduced levels of plasma aldosterone, failed to develop histologic lesions of malignant nephrosclerosis, and had marked reductions in the degree of proteinuria. However, despite concomitant ACE inhibition, the aldosterone-treated subgroup developed histologic and clinical characteristics comparable with those seen in the vehicle- and aldosterone-only stroke-prone spontaneously hypertensive subgroups. In this model, there is a clear role for aldosterone in the pathogenesis of vascular injury, and aldosterone-related injury is independent of the effects on blood pressure.

Figure 2.

Vascular pathology of malignant nephrosclerosis in saline-fed stroke-prone spontaneously hypertensive rats. Representative photomicrograph of renal cortex from saline-drinking stroke-prone spontaneously hypertensive after 2 weeks of treatment with vehicle or aldosterone. Typical lesions of malignant nephrosclerosis consist of ischemic or thrombotic glomeruli (large arrows), extensive mural fibrinoid deposits in microvessels (large arrowheads), and fragmented extravasated erythrocytes (small arrowheads). Reprinted with permission from Rocha et al³⁸.

Full figure and legend (123K)

Aldosterone in the L-NAME model

In a follow-up study, Rocha et al³⁹ examined the role of aldosterone in the development of renal injury and myocardial necrosis in another rat model. Hypertension was induced in male Wistar rats by a combination of sustained infusion of Ang II, infusion of an inhibitor of nitric oxide synthase, N-nitro-L-arginine methyl ester (L-NAME), and a high-sodium diet. In this model, the hypertensive animals developed fibrinoid necrosis of the renal arterioles and proteinuria plus biventricular myocardial hypertrophy and necrosis. To evaluate the role of aldosterone in mediating the cardiovascular changes, they performed an ablation/replacement experiment. Adrenalectomy or aldosterone blockade with administration of the selective aldosterone blocker eplerenone markedly reduced the cardiac and renal damage without significantly altering blood pressure. When adrenalectomized, glucocorticoid-replaced, L-NAME/Ang II/salt-treated animals were then infused with aldosterone, the cardiovascular damage was restored. This study provides further strong support for the independent role of mineralocorticoids in the genesis of hypertensive nephropathy and vascular injury.

ALDOSTERONE AND RENAL REMODELING

The vasculature is an integrated organ composed of endothelial cells, smooth muscle fibers, fibroblasts, and connective tissue. These elements are capable of identifying changes within their milieu and responding in an attempt to reestablish homeostasis. Vascular remodeling is an active process resulting in alterations in the growth, apoptosis, cell migration, and extracellular matrix due to an altered expression of growth factors, vasoactive substances, and mechanical factors⁴⁰. Acting through autocrine, paracrine, and endocrine pathways, aldosterone is increasingly being recognized as an important contributor.

The primary role of mineralocorticoid receptors

Mineralocorticoid receptors are present in vascular smooth muscle and endothelial cells⁴¹. The initial step in mineralocorticoid-induced vascular remodeling results from events triggered when aldosterone or other mineralocorticoids bind to mineralocorticoid receptors on vascular cells. Gavras et al⁴² used the well-established deoxycorticosterone acetate (DOCA) model to address the association of mineralocorticoid receptor activation and vascular response. In this model, hypertension is induced in uninephrectomized rats using DOCA and high salt intake. After a period of 3 to 4 weeks of positive sodium balance and rising blood pressure, a malignant phase developed that was marked by fibrinoid necrosis of renal arterioles. The cascade of events leading to the fibrinoid necrosis of the renal arterioles was clearly mineralocorticoid dependent. Wistar-Furth rats are resistant to the hypertensive effects of DOCA⁴³, reflecting a partial defect of mineralocorticoid responsivity in vascular smooth muscle and possibly the kidney. Ullian et al⁴³ demonstrated that aldosterone treatment of VSMCs cultured from these rats produced less smooth muscle contraction and regulation of angiotensin metabolism than in control wild-type Wistar rats.

PATHOLOGIC PROCESSES IMPLICATED IN ALDOSTERONE-INDUCED RENAL VASCULAR REMODELING

In addition to its classical effects on sodium and potassium transport in the renal tubule, newly emerging data are revealing a number of pathologic processes by which aldosterone mediates renal vascular remodeling Table 1. Although the molecular pathways of these processes have not been clearly elucidated, they all appear to contribute to the final common pathway of aldosterone-mediated renal vascular remodeling.

Table 1 - Possible pathways of mineralocorticoid-induced vasculopathy.

Full table

Plasminogen activator inhibitor-1

Increased levels of plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of the fibrinolytic system, appear to contribute significantly to aldosterone-mediated injury and fibrosis⁴⁴. In addition to its primary effects on the interactions between tissue plasminogen activator, urokinase, and plasminogen, PAI-1 also modulates extracellular matrix turnover and activation of latent growth factors. Increased levels of PAI-1 have been identified as a risk factor for coronary heart disease and are thought to contribute to the microcirculatory abnormalities of other diseases⁴⁵. Increased levels of PAI-1 also are centrally involved in the pathogenesis of both glomerulosclerosis and tubulointerstitial fibrosis⁴⁶. By interacting with Ang II, aldosterone increases PAI-1 expression in tissue cultures of endothelial cells as well as in vivo. This promotes the accumulation of extracellular matrix in blood vessels, glomeruli, and the heart.

There is a direct functional link between the RAAS, aldosterone, and the human fibrinolytic system. Levels of PAI-1 correlate significantly with aldosterone concentration during periods of low salt intake⁴⁷. Whereas both Ang II and aldosterone modulate PAI-1 expression, substantial evidence supports the role of aldosterone as a contributor to Ang II effects on fibrinolysis⁴⁸. In a rat model, radiation to the kidneys was followed by an eightfold increase in the expression of PAI-1 mRNA (P < 0.001)⁴⁴. Blockade of the RAAS with an ARB or aldosterone blockade with spironolactone significantly decreased the development of glomerulosclerosis and associated proteinuria. The renoprotective effects of mineralocorticoid receptor blockade may reflect, at least in part, down-regulation of PAI-1 expression.

TGF-

TGF- is a cytokine that promotes fibroblast differentiation and proliferation, up-regulates collagen synthesis and deposition, and down-regulates the release of the matrix metalloproteinase collagenase⁴⁹. Following blood vessel injury, Ang II generated at the damaged site stimulates synthesis of TGF-1. Uninephrectomized rats treated with aldosterone demonstrate increased binding density of ACE and Ang II receptors, increased expression of TGF-1 and collagen mRNAs, and diffuse renal medullary and cortical fibrosis accompanied by the accumulation of abundant myofibroblasts at the sites of fibrosis⁴⁹. Infusion of aldosterone induced these changes in the presence of AT1 receptor blockade with losartan, suggesting that aldosterone has an independent role in nephrosclerosis/glomerulosclerosis and RAAS-related TGF-1 release.

Reactive oxygen species

Superoxide anion, hydroxyl radicals, and hydrogen peroxide are reactive oxygen species that are produced in a number of disease states and have been implicated in a number of disease processes⁵⁰. They damage cells by peroxidation of the cell membrane lipids and by denaturing proteins. In an experimental stroke-prone spontaneously hypertensive rat model [abstract P4.03; Stier C, Jr., et al, Proc Int Soc Hypertens, August 23, 2000, Chicago, IL, USA], the RAAS was blocked by lisinopril, and aldosterone was infused following ACE inhibition. Infusion of aldosterone resulted in the development of renal vascular injury with thrombotic microangiopathy, tubular ischemia, and proteinuria. Because administration of scavengers of reactive oxygen species decreased kidney damage in this model, a component of mineralocorticoid-induced injury may have resulted from the generation of oxygen-free radicals and hydrogen peroxide.

Endothelial dysfunction

Nitric oxide of endothelial origin is a potent endogenous vasodilator. Although nitric oxide has several features, significant properties relevant to this discussion include the ability of nitric oxide to influence renal hemodynamics and tubuloglomerular feedback, inhibit matrix protein accumulation, and block the proliferation of smooth muscle cells and fibroblasts⁵¹. Sustained inhibition of nitric oxide synthase (NOS) can produce hypertension and vascular injury. In tissue culture, aldosterone decreases interleukin (IL)-1-stimulated nitric oxide bioactivity⁵².

Dysfunctional endothelial cells exhibit impaired nitric oxide–induced vasodilation. Endothelial dysfunction is a sign of a vascular injury and marks patients at risk for cardiovascular adverse events⁵³. It has been shown that aldosterone induces endothelial dysfunction in normal people. In a trial of 16 healthy volunteers⁵⁴, aldosterone infusion attenuated endothelium-dependent vasodilatation to acetylcholine compared with either prednisolone or placebo, whereas endothelium-independent vasodilatation was not affected by either hormone. Further, in patients with chronic heart failure, mineralocorticoid receptor blockade with spironolactone increased nitric oxide bioactivity, improved endothelial vasodilatory dysfunction, and suppressed the conversion of vascular ATI to Ang II⁵⁵. Endothelial dysfunction appears to be one of the mechanisms involved in the development of microalbuminuria through alterations in the permselectivity of the glomerular basement membrane⁵⁶.

The relative contributions of aldosterone and glucocorticoid binding to mineralocorticoid receptors in endothelial dysfunction is an interesting question. Because mineralocorticoid receptors have similar affinities for corticosterone, cortisone, and aldosterone—and circulating levels of these glucocorticoids are in great excess of plasma aldosterone levels—aldosterone must bind to mineralocorticoid receptors against stoichiometric odds. One strategy used in vascular tissues to regulate cellular glucocorticoid concentrations is through the activity of 11-hydroxysteroid dehydrogenase type 2 (11-HSD2). This enzyme inactivates glucocorticoids, thereby increasing the probability of aldosterone binding to mineralocorticoid receptors^57,58.

In the absence of the enzyme, the relative excess of glucocorticoids to mineralocorticoids can produce hypertension. Glycyrrhizic acid (GA), found in liquorice, is a potent inhibitor of 11-HSD2. In a rat model of GA-induced hypertension, mineralocorticoid receptor antagonism with spironolactone prevented upregulation of endothelin-1, a potent vasoconstrictor; completely restored nitric oxide–mediated endothelial function; and normalized blood pressure⁵⁹.

Alterations in VSMCs

Aldosterone has multiple actions at the level of VSMCs. These effects can lead to hypertension and increased vasoreactivity and peripheral vascular resistance. For example, aldosterone may potentiate the pressor responses to Ang II by significantly up-regulating the number of Ang II receptors and releasing intracellular calcium stores⁶⁰. Aldosterone also directly influences the movement of sodium ions across the VSMC membrane by up-regulating the synthesis of sodium channels, which may contribute to vascular hyperreactivity in disorders of mineralocorticoid excess⁶¹. Aldosterone also inhibits the uptake of norepinephrine by VSMCs. In combination with the aldosterone-mediated decrease in cardiac myocyte norepinephrine uptake, this has the potential to lead to ventricular arrhythmias. Mineralocorticoid receptor blockade with spironolactone can normalize this dysfunction⁶². Aldosterone also significantly enhances the Ang II-induced increase in [³H]leucine incorporation in smooth muscle cells; this process is inhibited by ZK 91587, a type 1 mineralocorticoid receptor antagonist⁶³. These metabolic effects indicate that aldosterone may directly participate in the hypertrophy and dysfunction of VSMCs.

ALDOSTERONE BLOCKADE AND PREVENTION OF RAAS-INDUCED NEPHROPATHY

Evidence from various rat models reviewed above indicates that aldosterone plays a major role in sustaining hypertension and promoting fibroproliferation and destruction of the kidneys. As in animal studies, elevated levels of aldosterone occur in patients with chronic renal disease and appear to be independent of plasma potassium concentration and plasma renin activity (PRA). In a study of 28 patients with varying degrees of renal dysfunction and comparable serum potassium and PRA levels, plasma aldosterone generally was elevated when creatinine clearance was lower than 50% of normal⁶⁴.

The relationship of primary aldosteronism, renal injury, and cardiovascular risk also has been evaluated. During the decade after he first reported a case of a patient with an aldosterone-secreting adrenal tumor, Conn, Knopf, and Nesbit⁴ found that 85% of patients with primary aldosteronism also have proteinuria, a significant risk factor for cardiovascular events. It is not surprising that a Japanese study recently reported that in a group of 58 patients with an adrenal cortical adenoma and primary aldosteronism, cardiovascular complications were identified in 34%⁶⁵. The most common indicator of mineralocorticoid-induced vasculopathy was proteinuria, identified in 24% of patients. In male patients older than 40 years of age, proteinuria was significantly associated with the occurrence of stroke (P = 0.03). These findings provide further evidence that the aldosterone-induced renal vascular injury is indicative of pathology in other vascular beds.

Does mineralocorticoid receptor antagonism have clinical benefits? Until recently, spironolactone, a nonspecific aldosterone receptor blocker, was the only agent of this class clinically available. Preliminary data indicate that spironolactone decreases proteinuria in patients with both chronic renal disease⁶⁶ and those with type 2 diabetes and early nephropathy⁶⁷. The use of spironolactone is limited by the prevalence of adverse sexual effects. The increased selectivity of eplerenone, recently approved for use by the federal Food and Drug Administration, allows for clinical efficacy without the unwanted side effects⁶⁸.

Data regarding eplerenone safety and efficacy are beginning to emerge with three studies recently presented. However, the results have only been reported in abstract form and renal effects were not primary end points in two of these studies. Epstein et al [abstract; Epstein M, et al, J Am Coll Cardiol 39:Suppl A, 2002] evaluated eplerenone, enalapril, and a combination of both agents in 266 patients with type 2 diabetes mellitus, mild-to-moderate hypertension, and proteinuria [urinary albumin:creatinine ratio (UACR) 100 mg/g] during a 24-week, double-blind study. Eplerenone decreased microalbuminuria independent of its antihypertensive activity. Compared with enalapril, the renoprotective properties of eplerenone were significantly better by week 24. UACR was reduced by 62% (95% CI, 53%–69%) in the eplerenone group and by 45% (95% CI, 32%–55%) in the enalapril group (P = 0.015 between groups). However, the reduction in albumin excretion with combination therapy was significantly more effective than monotherapy with either drug. UACR was reduced by 74% (95% CI, 67%–79%) in the eplerenone/enalapril group (P = 0.018 vs. eplerenone; P < 0.001 vs. enalapril) Figure 3. Elevated potassium levels (6 mEq/L) were observed in eight eplerenone patients, two enalapril, and eight eplerenone/enalapril patients. More patients were withdrawn for hyperkalemia in the eplerenone/enalapril group (N = 14) than in the eplerenone group (N = 6) or the enalapril group (N = 2). A subsequent follow-up study is being conducted to determine if lower doses of eplerenone will maintain reductions in albumin excretion without substantially increasing potassium levels.

Figure 3.

Percent change in urinary albumin:creatinine ratio at week 24 in eplerenone, enalapril, and eplerenone/enalapril patients.*P < 0.001 week 24 vs. baseline for all treatments [abstract; Epstein M, et al, J Am Coll Cardiol 39:Suppl A, 2002].

Full figure and legend (14K)

In another study, Burgess et al [abstract; Burgess E, et al, Am J Hypertens 15:23A, 2002] compared antihypertensive efficacy and safety of eplerenone and enalapril in the treatment of patients with mild-to-moderate hypertension. Among the subset of patients (number of patients not stated) with microalbuminuria at baseline (UACR 30 mg/g), the mean percent reduction in albumin excretion achieved by eplerenone was significantly superior to that of enalapril (61.5% vs. 25.7%; P = 0.01) and was independent of blood pressure reduction. Another abstract has suggested that eplerenone and enalapril reduce UACR from baseline values and that the combination of the two drugs produces additive benefit among patients with hypertension and left ventricular hypertrophy [abstract; Pitt B, et al, Am J Hypertens 2002:15:23A-24A, 2002]. However, this preliminary report is not sufficiently detailed to make a proper interpretation.

CONCLUSION

A growing body of preclinical and clinical evidence supports the role of aldosterone as an independent and powerful mediator of renal vascular remodeling and in the progression of both hypertensive renal vascular disease and diabetic nephropathy. Although multiple aldosterone-mediated mechanisms appear to contribute to renal vascular injury, a specific, final, common pathway is yet to be clearly defined.

Whereas aldosterone blockade with spironolactone as a therapeutic option has been limited by its lack of specificity, clinical and experimental evidence indicate that aldosterone antagonism can protect the kidneys and decrease proteinuria, a surrogate marker of renal injury and cardiovascular risk. Use of eplerenone—alone or in combination with other inhibitors of elements of the RAAS—can decrease the incidence of adverse events associated with nonselective aldosterone blockade, provide effective blood pressure control, and increase efficacy in combination therapy. Clearly, enough has been learned to justify, indeed mandate, the clinical trial necessary to prove the therapeutic efficacy.

References

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Acknowledgments

Personal research cited in this essay was supported in part by the National Institutes of Health grants (NCRR GCRC M01RR02636, Hypertension SCOR 5P50HL55000, Hypertension Training T32HL07609, and 1R01DK5466804).